The Jets opened their 2012 season against the Buffalo Bills with Sanchez completing 19 of his 27 passes for 266 yards, 3 touchdowns and an interception in a 48–28 rout of the Bills. In the subsequent four games, Sanchez became the first quarterback since Stoney Case in 1999 to complete under 50% of his passes in four straight contests as the Jets fell to a 2–3 record. This led to fierce criticism from the media and fans and prompted calls for Sanchez to be benched in favor of Tim Tebow. Sanchez snapped this streak against the Indianapolis Colts on October 14, 2012 completing 11 of his 18 passes for 82 yards and throwing for 2 touchdowns in a 35–9 victory over Indianapolis.

Prior to his junior year of high school, Sanchez transferred to Mission Viejo, where Johnson, who was recognized as a “quarterback guru”, having trained professionals like Carson Palmer, was head coach. Under Johnson’s tutelage, Mark felt he would have a better opportunity to become a better player. Johnson tutored Mark on the complexities of the position and in two seasons with the team, Mark led the Diablos to a 27–1 record culminating with the California Interscholastic Federation Division II championship in 2004.

Sanchez was named football player of the year by several major college recruiting services and was considered the top quarterback in the nation upon the conclusion of his high school football career in 2005. In July 2004, Sanchez announced his commitment to the University of Southern California.

Being named the nation’s top quarterback coming out of high school, Sanchez was well regarded upon his arrival at USC. With upperclassmen Matt Leinart and John David Booty returning, Sanchez did not play during his freshman year in 2005, opting to redshirt to preserve a year of eligibility. During this time, he participated as the quarterback of USC’s scout team, earning the Trojans’ Service Team Offensive Player of the Year Award.

In April 2006, Sanchez was arrested after a female USC student accused him of sexual assault. He was released from jail the following day and suspended. On June 3, 2006, the Los Angeles County District Attorney’s office announced no charges would be filed, and Sanchez was reinstated, though he was disciplined by the football team for underage drinking and using false identification on the night he was arrested.

Sanchez entered spring practice after the 2008 season as the front-runner to take over the starting quarterback position, but faced strong competition from redshirt freshman Aaron Corp and Mitch Mustain, a transfer from Arkansas, where he had been the starting quarterback; Mustain, like Sanchez, was named the top quarterback in the nation upon the conclusion of high school career in 2006. By the end of spring practice, Carroll announced Sanchez would be the starting quarterback heading into the fall. During the first week of fall camp, Sanchez dislocated his left kneecap during warm-ups prior to practice; trainers immediately put the kneecap back into place. After missing nearly three weeks, Sanchez was cleared to play in the opener against Virginia. Before the opener, Sanchez was contacted by USC’s previous three quarterbacks—Carson Palmer, Leinart and Booty—who wished him well and offered general advice.

While starting for an injured John David Booty in 2007, Sanchez wore a custom mouthguard that featured the colors of the Mexican flag in honor of his heritage. It became a prominent issue after a nationally televised game against Notre Dame. The mouthpiece became a symbol for two opposing viewpoints: for Mexican-Americans, it was a symbol of unity—Sanchez accepting his heritage; for critics, the gesture symbolized a radical political statement. Sanchez, who was born and raised in the United States, received hate mail urging him to return to Mexico. Sanchez responded to the controversy stating, “It’s not a Mexican power thing or anything like that. It’s just a little bit of pride in our heritage. Hopefully, it inspires somebody and it’s all for the best.” Overwhelmed by the attention and shying away from politics, Sanchez stopped wearing the mouthpiece, but began participating in other efforts to help the Hispanic community.

The New York Jets drafted Sanchez in the first round using the fifth overall selection in the 2009 NFL Draft, making him the first quarterback selected by the Jets in the first round since Chad Pennington went 18th overall in the 2000 NFL Draft. To select Sanchez, the Jets traded their first and second round selections and three players, Kenyon Coleman, Abram Elam and Brett Ratliff, to the Cleveland Browns. At the time, the selection was lauded as good value for the team and for Sanchez. Sanchez reached an agreement with the team on June 10, 2009, signing a five-year, $50 million contract, with $28 million guaranteed. It is the largest contract the Jets signed a player to in franchise history.

Heading into his rookie training camp, Sanchez was listed as the second quarterback behind veteran Kellen Clemens. Jets head coach Rex Ryan viewed the camp as an opportunity for both quarterbacks to compete against each other to determine the eventual starter for the 2009 season. On August 26, 2009, Sanchez was named the starter, becoming the first rookie quarterback to start the season for the team since Dick Jamieson in 1960.

Sanchez started his first regular season NFL game against the Houston Texans on September 13, 2009, throwing his first touchdown pass, a 30-yard reception, to wide receiver Chansi Stuckey. Sanchez and the Jets won the game 24–7, with Sanchez throwing for 272 yards, a touchdown, and an interception. He was named the Pepsi Rookie of the Week for his performance in the game, the first of three consecutive Rookie of the Week awards. He played his first home game a week later versus the New England Patriots, a 16–9 victory; it was also his first AFC East division game and his first rivalry game. It was the Jets’ first victory over New England at home since 2000. With a 24–17 victory over the Tennessee Titans in Week 3, Sanchez became the first rookie quarterback in NFL history to start and win his first three games of an NFL season. However, his performance began to regress as he had a pass intercepted for a 99-yard touchdown return, and fumbled another attempted pass in the end zone for another touchdown, as the Jets fell to the New Orleans Saints in Week 4. These two plays were enough to spoil an otherwise strong outing from the Jets’s defensive unit as the team dropped to a 3–1 record. Following the loss to New Orleans, Sanchez received criticism in a 16–13 overtime loss to the Buffalo Bills in Week 6 when he threw five interceptions against a lowly Bills defense that previously had only four interceptions all season long. The Jets ended their losing streak in a 38–0 victory against the Oakland Raiders in Week 7 however, Sanchez was criticized after he was seen eating a hot dog on the Jets’ bench in the fourth quarter.

In the team’s second meeting against the Bills on December 3, 2009, Sanchez suffered a sprained posterior cruciate ligament in the third quarter, prompting the veteran Clemens to take his place. Though there were no setbacks to the injury, head coach Ryan benched Sanchez the following game against the Tampa Bay Buccaneers for precautionary reasons, much to Sanchez’s dismay. At 7–7, the Jets had a chance to secure a playoff berth if they won the remainder of their games. One such game was against the Indianapolis Colts who had 23 consecutive regular season wins. Sanchez and the Jets engineered a comeback win following Colts head coach Jim Caldwell’s decision to controversially rest the team starters in the third quarter with a five-point lead. The following week, on January 3, 2010, Sanchez led the team into the playoffs, despite a subpar effort, completing 8-of-16 passes for 63 yards, en route to a 37–0 victory over the Cincinnati Bengals, who rested their starters as the team had already clinched the AFC North division title and a playoff berth. The manner of the two wins, which gave the Jets their first playoff berth since 2006, caused many to claim the team had “backed into the playoffs”. Sanchez completed his rookie season with 2,444 yards, 12 touchdowns, and 20 interceptions.

In the Wild Card Round, that took place on January 9, 2010 at Paul Brown Stadium, Sanchez led the Jets to another victory over the Bengals, 24–14, behind his positive performance where he completed 12 of his 15 passes while throwing for 182 yards and a touchdown with a passer rating of 139.4. Sanchez became the fourth rookie quarterback in NFL history to win his first postseason contest, and the second to do so on the road. The others were Shaun King (1999 Bucs), Ben Roethlisberger (2004 Steelers), and Joe Flacco (2008 Ravens). On January 17, 2010, Sanchez, with the help of running back and fellow rookie Shonn Greene, defeated the heavily favored San Diego Chargers 17–14 to attain the Jets’ third AFC Championship appearance in franchise history. Sanchez became only the second rookie quarterback to win two consecutive playoff games, behind Joe Flacco. In a rematch of their regular season meeting with the Colts, Sanchez performed well in the first half however, the offense succumbed to the Colts’ defense in the second half and the Jets gave up an 11-point lead, losing by a score of 30–17. Sanchez was named to Sporting News’ All-Rookie team for his performance during the season, becoming the first Jets quarterback to ever receive the award.

On February 17, 2010, Sanchez underwent surgery to repair the patella ligament in his left knee that he originally injured when he played for USC. The surgery was successful. Sanchez was expected to miss early workouts and return in time for training camp however Sanchez made a quick recovery and participated in team drills during Organized Team Activities (OTA). The Jets opened the 2010 season with a 5–1 record despite the passing game being subpar as Sanchez struggled to accurately throw the football. Sanchez recorded his first career 300-yard passing game in a win over the Detroit Lions on November 7, 2010. At 10–4, the Jets faced the Chicago Bears on December 26, 2010 with a chance to clinch a playoff berth. Though Sanchez injured his shoulder in a victory over Pittsburgh the previous week, he started the game completing 24 of his 37 passes for a touchdown and an interception. However, the Jets were unable to defend the Bears’ offense and subsequently lost the game 38–34 after a comeback drive was halted when Sanchez was intercepted. Fortunately for them, due to a loss by the Jacksonville Jaguars that same day, the Jets clinched the playoff berth. Sanchez finished the season with 3,291 yards, 17 touchdowns, and 13 interceptions.

Early in his career, Sanchez was praised for his ability to maintain composure in the pocket amidst defensive pressure and focus on finding an open receiver to extend the team’s offensive series. In his first four years, Sanchez had ten fourth quarter comebacks and twelve game winning drives. These characteristics were highlighted by Bill Parcells and Sam Wyche and garnered comparisons to Ben Roethlisberger. Sanchez was also noted for his proficiency in short passing situations and competitive nature; in December 2010, following dismal performances, Rex Ryan threatened to reduce Sanchez’s repetitions with the first team offense during practice which infuriated Sanchez.

While Sanchez has embraced a playboy lifestyle, drawing comparisons to former Jet Joe Namath, he was praised by Brian Schottenheimer for his ability to work with various personalities and build relationships with teammates. After undergoing knee surgery following his rookie season, Sanchez established “Jets West” in 2010, an annual off-season camp located in his home state of California. Sanchez hosts workouts and offers classroom review sessions for his skill-position teammates on offense for one week. During the NFL labor dispute, Sanchez managed to organize private workouts with over forty of his teammates.

Sanchez is an avid fan of musical theatre. He was a presenter at the 2010 Tony Awards, where he introduced a number from the Broadway musical Memphis. Sanchez has been involved in multiple charities including the Juvenile Diabetes Research Foundation to help raise awareness for Type 1 diabetes and Sam’s Club’s Giving Made Simple which, helps raise awareness about childhood obesity and how families can prevent it. Sanchez has also worked with the Teddy Atlas Foundation through which he met Aiden Binkley, a terminally ill 11-year-old struck with rhabdomyosarcoma. Sanchez developed a bond with Binkley and the two remained close friends until Binkley’s death in December 2010.

The Jets finished the season with an 11–5 record and entered the wild card round facing the Indianapolis Colts in a rematch of their previous encounter in the AFC Championship. Although Sanchez had a subpar performance completing 18 of his 31 passes while throwing an interception, he led the team in the final minutes of the game on a comeback drive culminating with kicker Nick Folk kicking the game-winning field goal as time expired. The Jets went on to face the New England Patriots in the divisional round and upset the heavily favored Patriots, 28–21, as Sanchez completed 16 of his 25 passes for 194 yards and three touchdowns. With the win, Sanchez tied Len Dawson, Roger Staubach, Jake Delhomme, and Joe Flacco for the second most post-season road victories by a quarterback in NFL history. The team traveled to the AFC Championship, for a second consecutive season, to face the Pittsburgh Steelers on January 23, 2011.

Sanchez, who knew how to speak some Spanish but was not fluent, began to take Spanish lessons during his junior year at USC so he could have conversations without the use of a translator. The USC band played “El Matador” when Sanchez would come onto the field. Sanchez participated in a fundraiser to help provide school supplies to first-graders in the city of Long Beach and region of South Bay, and helped Mayor Antonio Villaraigosa give holiday gifts to impoverished families. By the end of his USC career, he had been hailed as a role model for Hispanic youth. Sanchez serves as the Ambassador to the Inner-City Games Los Angeles, an after-school program that provides “at-risk youth” with positive, alternative activities. ESPN Radio came to an agreement with the Jets to broadcast all of the team’s regular season games in 2011 on 710 ESPN Radio in Los Angeles. The agreement came about due to Sanchez’s continued popularity in California.

Prior to the outset of the 2011 season, head coach Rex Ryan named Sanchez a team captain. The Jets opened the season with a 2–3 record leading to discontent within the clubhouse. The team had begun to stray from their philosophy of consistently running the ball and began to pass more often; however, the offense struggled with this adjustment. Wide receivers Plaxico Burress, Santonio Holmes, and Derrick Mason approached coach Ryan to question offensive coordinator Brian Schottenheimer’s system as Holmes and Mason averaged only three catches per game and Burress only 2.5 catches through four games. Additionally, Sanchez drew criticism for his difficulties to effectively throw the ball to his receivers. The struggles culminated with Holmes getting into a heated argument with another teammate in the huddle during their final regular season game against the Miami Dolphins. Holmes was benched in the fourth quarter while Sanchez threw three interceptions in the Jets’ loss that eliminated the team from playoff contention for the first time in Sanchez’s career. Statistically, Sanchez had similar numbers in a comparison to Eli Manning when he concluded his third year of football however, there were concerns that Sanchez was simply an ineffective quarterback and therefore expendable. During the offseason, Sanchez was criticized by anonymous teammates for his poor work ethic and his inability to improve; these claims were publicly refuted by other teammates. Despite questions surrounding his job security, after New York acquired Tim Tebow, the Jets agreed to a 3-year contract extension with Sanchez on March 9, 2012. The contract included $20 million in guarantees.

Sanchez started the next week, but was benched in the third quarter of the Jets’ contest against the Arizona Cardinals on December 2, 2012 in favor of third string back-up Greg McElroy. Prior to being benched by Rex Ryan, Sanchez threw three interceptions. McElroy threw a touchdown to tight end Jeff Cumberland to score the team’s only points in a 7–6 victory over Arizona. Rex Ryan renamed Sanchez the starting quarterback the following Wednesday after seeking out multiple opinions within the organization. Sanchez returned to complete 12 his 19 passes for 111 yards against the Jacksonville Jaguars, fumbling once that led to a Jaguar field goal. The Jets won 17–10. In a must-win game against the Tennessee Titans to remain in playoff contention, Sanchez struggled; he completed 13 of his 28 passes for 131 yards while throwing four interceptions and fumbling the ball in Titans territory in the closing minutes of the Jets’ 14–10 defeat. A day later, Ryan named McElroy the starter. Sanchez started the Jets’ final game against the Buffalo Bills after McElroy revealed he had been experiencing concussion symptoms in the days preceding. The Jets were defeated 28–9 with Sanchez completing 17 of his 35 passes for 205 yards and two turnovers.

In December 2012, following a series of poor performances that eventually led to his benching, a panel of former NFL quarterbacks were questioned about Sanchez’s different attributes. It was unanimously agreed upon that his arm strength was “good enough” to succeed in the league and that he could be effective while mobile in the pocket. His regression was mainly attributed to his poor accuracy, a byproduct of his indecisive mentality once the ball is snapped, and the fact the Jets did little to help surround Sanchez with the talent to overcome his shortcomings. Ron Jaworski commented that Sanchez had lost his confidence which contributed to his decline.

Sanchez suffered a shoulder injury on August 24, 2013 in the Jets’ third game of the preseason against the New York Giants after being tackled by nose tackle Marvin Austin. The Jets, who drafted rookie quarterback Geno Smith in the 2013 NFL Draft, named Smith the starter on September 4 with Sanchez still rehabilitating his injury. On September 14, 2013, Sanchez was placed on injured reserve with a designation to return. After undergoing shoulder surgery on October 8, 2013, it was announced he would miss the rest of the season. After much speculation regarding his future in New York, the Jets released Sanchez on March 21, 2014, the same day the Jets signed Michael Vick, the former Atlanta Falcons and Philadelphia Eagles quarterback.

Sanchez signed with the Philadelphia Eagles on March 29, 2014, for a 1-year, $2.25 million contract. After spending seven full games as Nick Foles’s backup, Sanchez filled-in for an injured Foles, in a Week 9 game against the Houston Texans. Throwing for 202 yards, 2 touchdowns, and 2 interceptions, Sanchez led the Eagles to a 31–21 win. After the game, Eagles head coach, Chip Kelly, praised Sanchez, saying, “He’s a hell of a quarterback and we’re excited that we got him.” Foles was later confirmed to be out for 6 to 8 weeks with a broken collarbone, meaning Sanchez would take over as the team’s quarterback.

On November 10, 2014, Sanchez started his first game for the Eagles and led them in a 45–21 rout of the visiting Carolina Panthers on Monday Night Football. Even though it was his first start at quarterback since December 2012, Sanchez notched two touchdowns as he threw for 332 yards—the fourth highest total in his NFL career. The victory also marked the first time he had ever thrown for more than 265 yards without an interception. Sanchez followed this with a 53–20 loss against Green Bay, where he threw for 346 yards and 2 touchdowns, but was also intercepted twice and lost 2 fumbles. Sanchez came back with 2 consecutive wins, a 43–24 rout of the Titans where he threw for 300 yards in his third consecutive start, and a 33–10 win against the Cowboys on Thanksgiving, where he logged 207 yards and a touchdown as well as 28 rushing yards and a score. With the Eagles at a 9–3 record, and his record as a starter at 3–1, the Eagles looked poised to win the NFC East, but after 3 consecutive losses and playoff elimination, he finished the 2014 season with a 4–4 record as the Eagles starting quarterback. In 9 games and 8 starts, he threw for 2,418 yards, 14 touchdowns, 11 INTs, and a 64.0 completion percentage, while rushing for 87 yards and 1 touchdown, with a career-high 88.4 passer rating.

The Eagles re-signed Sanchez to a two-year, $16 million contract on March 8, 2015, but despite his play in the 2014 season, he remained the backup quarterback as Nick Foles was traded for Sam Bradford. In Bradford’s first several games, he had thrown more interceptions than touchdowns and often had a low completion percentage, but head coach Chip Kelly refused to bench Bradford in favor of Sanchez. Ironically, Sanchez would get his first playing time when Bradford was playing his best football of the season.

On November 15, 2015, Sanchez came into a Week 10 game against the Miami Dolphins in relief of injured starter Sam Bradford with the Eagles trailing 20–16 late in the 3rd quarter. Sanchez finished 14–23 with 156 yards and an interception. The interception was costly as it occurred in the endzone when the Eagles were in field goal range down 20–19, which ended up being the final score of the game.

On March 11, 2016, Sanchez was traded to the Denver Broncos for a 2017 conditional draft pick. Prior to his arrival to the Broncos, Peyton Manning had retired and Brock Osweiler had signed with the Houston Texans. This opened up a competition for the Broncos starting quarterback job between Sanchez, second-year player Trevor Siemian and rookie Paxton Lynch. On August 29, Broncos head coach Gary Kubiak named Siemian the starting quarterback for the 2016 season. On September 3, 2016, Sanchez was released by the team.

On September 3, 2016, hours after the Broncos released him, Sanchez signed a one-year $2 million contract with the Dallas Cowboys, who were looking to have a veteran presence behind rookie Dak Prescott, who was named the starter at quarterback while Tony Romo recovered from a vertebral compression fracture he suffered during the first quarter of the Cowboys’ Week 3 preseason game against the Seattle Seahawks. In Week 17, with the Cowboys already having clinched the NFC’s #1 seed, Sanchez split time with starter Prescott and backup Romo. Prescott played the first two series of the game, Romo played the third, and Sanchez played the rest of the game. Sanchez completed 9 of 17 passes for 85 yards with two interceptions as the Cowboys lost to the Philadelphia Eagles by a score of 27–13.

In June 2016, a lawsuit filed by U.S. Securities and Exchange Commission alleged that Sanchez’s broker conducted a “ponzi-like scheme” which defrauded Sanchez, as well as Roy Oswalt and Jake Peavy, out of US$30 million.

On March 23, 2017, Sanchez signed a one-year contract with the Chicago Bears. The Bears had noted the “positive influence” Sanchez had as a mentor to rookie quarterback Dak Prescott and looked for him to play a similar role in the development of rookie Mitchell Trubisky. On May 30, 2017, Sanchez suffered a small knee injury in his left knee. He missed the remainder of OTA’s and the minicamp. In response, the Bears rescinded the waiver request to Connor Shaw following the injury to Sanchez. Sanchez made the Bears’ final roster third on the quarterback depth chart behind Trubisky and Mike Glennon, but did not play at all in 2017. On April 13, 2018, Sanchez, while still a free agent, was suspended for four games for violating the NFL’s performance-enhancing drug policy. Sanchez tested positive for performance-enhancing drugs and cited “unknowing supplement contamination” in his statement to the media following the suspension.

On November 19, 2018, Sanchez signed with the Washington Redskins to serve as the backup to Colt McCoy, after starter Alex Smith suffered a season-ending leg injury. Sanchez made his first appearance with the Redskins for an injured McCoy in a 28–13 loss to his former team, the Philadelphia Eagles. He completed 13 passes from 21 attempts for 100 yards and an interception. Sanchez became the starter after McCoy fractured his fibula in the game. In Week 14, Sanchez was benched at halftime in a 40–16 loss to the New York Giants in favor for Josh Johnson, after throwing two interceptions and only 38 yards in the first half. The next day, the Redskins named Johnson their starter for the Week 15 game against the Jacksonville Jaguars.

Sanchez announced his retirement on July 23, 2019, and subsequently took a position with ESPN’s college football coverage.

On October 15, 2020, Sanchez was revealed to have competed on season four of The Masked Singer performing as the “Baby Alien”, the show’s first costume to incorporate a puppet. As Nick Cannon had a hard time figuring out how to remove Baby Alien’s mask upon elimination, he had to receive help from the Men in Black to do the job.