Romo started as quarterback for the Burlington High School Demons beginning as a junior (1996 season). In the 1997 season, Romo and the Demons finished with a 3–6 record, though he earned several honors, including the All-Racine County football team and Wisconsin Football Coaches Association All-State first team honors. Romo also was a starter on the Burlington High School varsity basketball team and also played golf and tennis. Romo graduated from Burlington High School in 1998.

Romo attended Eastern Illinois University in Charleston, Illinois, where he played for the NCAA Division I-AA Eastern Illinois Panthers football team and was a member of Sigma Pi. As a sophomore in 2000, he ranked second in Division I-AA in passing efficiency, completing 164-of-278 (59%) passes for 2,583 yards and 27 touchdowns. After the season, he was honored as an All-America honorable mention, an All-Ohio Valley Conference member, and the OVC Player of the Year. As a junior, he led Division I-AA in passing efficiency, completing 138-of-207 passes for 2,068 yards and 21 touchdowns.

Romo earned OVC Player of the Week honors on October 14, 2002, after his eight-yard scramble run on the last play of the game led Eastern Illinois to a 25–24 win over Eastern Kentucky.

On December 19, 2002, Romo became the first player in Eastern Illinois and Ohio Valley Conference history to win the Walter Payton Award, given annually to the top Division I-AA football player. He finished his career holding school and conference records with 85 touchdown passes. He finished second in school and third in conference history with 8,212 passing yards and second in school history with 584 completions and 941 attempts. As a senior, he set school and conference records for completions with 258 in 407 attempts for 3,418 yards. This was second in conference and third in school history for a season. He threw for 34 touchdowns and scored one rushing touchdown. Romo’s 3,149 yards in total offense as a senior ranked third in school and conference history. Along with the Walter Payton Award, Romo earned consensus All-America honors. In addition, he was selected All-Ohio Valley Conference and was named OVC Player of the Year for the third straight year.

Romo aided the Cowboys in clinching a playoff spot, their second since Parcells became coach in 2003. He concluded the 2006 regular season with 220 completions on 337 pass attempts for 2,903 yards, 19 touchdowns, and 13 interceptions, with a passer rating of 95.1.

Romo did not initially receive an invitation to attend the 2003 NFL Combine, but received a late invitation to attend as an extra quarterback to throw passes to other prospects during drills. Despite intriguing some scouts, he went undrafted by any NFL team during the 2003 NFL Draft. Throughout the draft, Romo was assured by Sean Payton of the Cowboys’ interest (Romo was also intensely pursued by Denver Broncos head coach Mike Shanahan), and shortly afterwards was signed as an undrafted rookie free agent by the Cowboys. Romo entered the 2003 training camp third on the Cowboys’ depth chart behind Quincy Carter and Chad Hutchinson. In 2004, the Cowboys released Hutchinson and signed veteran quarterback Vinny Testaverde and traded a third-round draft pick to the Houston Texans for quarterback Drew Henson. Romo faced being cut from the roster until Carter was released following allegations of substance abuse. Throughout 2004 and 2005, Romo served as the holder for placekicks. After Vinny Testaverde’s tenure in Dallas ended in 2005, the Cowboys signed veteran quarterback Drew Bledsoe, the team’s eighth starting quarterback since 2000.

One of Romo’s early career highlights was in 2004, when (as the third-string quarterback) he rushed for the winning touchdown with six seconds left in a preseason game against the Oakland Raiders. Elevated to the Cowboys’ second quarterback in 2005, Romo had strong showings in the 2005 and 2006 pre-seasons. In the 2006 off-season, Sean Payton (now head coach of the New Orleans Saints), offered a third-round draft pick for Romo, but Cowboys’ owner Jerry Jones refused, asking for no less than a second-round draft pick.

One week later on October 23, 2006, Romo replaced Bledsoe for the start of the second half of a game against the New York Giants. His first pass was tipped and intercepted. His game stats in only his second NFL appearance were 14 completions on 25 attempts for 227 yards, two touchdowns, and three interceptions (one of which was returned for a touchdown). On October 25, Cowboys head coach Bill Parcells announced that Romo would be the Cowboys starting quarterback for the October 29 game against the Carolina Panthers on NBC Sunday Night Football, in Week 8 of the 2006 season. Romo led the Cowboys to victory in his first game as a starter, 35–14. In that game, Romo was Sunday Night Football’s “Rock Star of the Game.”

On November 19, 2006, Romo led the Cowboys past the Indianapolis Colts, the NFL’s last unbeaten team. He completed 19 of 23 passes as the Cowboys won against the Colts 21–14. Four days later he helped the Cowboys win in a Thanksgiving Day game against the Tampa Bay Buccaneers by the score of 38–10. Romo went 22–29 with 306 yards and five touchdown passes and no interceptions. For his performance, he was awarded FOX’s Galloping Gobbler award as the Thanksgiving Day MVP.

In week 15, Romo led the Cowboys to a win against an undefeated team late in the season for the second time in his career. In 2006, he won against the 9–0 Indianapolis Colts, and on December 19, 2009, he defeated the 13–0 Saints at New Orleans, throwing for 312 yards, one touchdown and no interceptions.

The Cowboys played the Seattle Seahawks in the NFC Wild Card playoff round on January 6, 2007. With the Cowboys trailing 21–20 on fourth-and-one with 1:19 left in the game, the Cowboys attempted a 19-yard field goal. Romo, the holder for the kick, fumbled the snap. He recovered the ball and attempted to run it in, but was tackled short of the first down marker, and turned the ball over on the Seattle 2-yard line. The Cowboys went on to lose the game. Romo finished the 2006 season ranked seventh in the NFC in passing yards (2,903) and touchdown passes (19).

Romo played in the 2007 Pro Bowl after Drew Brees went down with an elbow injury as a substitution for Marc Bulger. He threw one touchdown and one interception, and was the NFC’s kickoff holder in the game.

Romo began the 2007 season with four touchdown passes and an additional touchdown rush, the first of his career, defeating the New York Giants 45–35 in the Cowboys’ first game of the regular season. His 345 passing yards in Week 1 led the NFL. In Week 2, he threw for 186 yards and two touchdowns beating the Miami Dolphins, ranking him seventh in passing yards and tied for second with six touchdown passes. Romo added 329 passing yards and two touchdown passes in the Cowboys’ Week 3 34–10 win over the Chicago Bears. The following week, he passed for 339 yards and three touchdowns in a 35–7 win over the St. Louis Rams. He also ran for an additional touchdown. This brought his season totals to 1199 passing yards with 11 passing touchdowns and two rushing touchdowns. In September 2007, Romo’s father was diagnosed with prostate cancer. Romo stated that, while upset about the family crisis, he still had to continue to focus on his career.

In November 2007, Romo began dating American singer and actress Jessica Simpson. On December 16, 2007, Simpson attended a Dallas Cowboys–Philadelphia Eagles game at Texas Stadium, in which Romo had a bad performance in the loss to the Eagles. Controversy erupted before the playoff game against the New York Giants—a game the Cowboys would lose—when pictures surfaced of Romo (along with teammates Jason Witten and Bobby Carpenter) at a resort in Cabo San Lucas with Simpson. On July 13, 2009, People reported that Romo and Simpson had broken up on July 9, 2009—the night before her 29th birthday.

On September 7, 2008, Romo led the Cowboys to a 28–10 win over the Cleveland Browns in their season opener. Romo completed 24 of his 32 passes for a total of 320 yards and one touchdown. After the game, Romo required 13 stitches for a large gash on his chin that occurred during the third quarter when linebacker Willie McGinest hit him in the chin with his helmet. The NFL fined McGinest $7,500 for the hit.

Romo is an avid amateur golfer, and attempted to qualify for the 2004 EDS Byron Nelson Championship and the 2005 U.S. Open, but failed. During the offseason, when not training, he plays golf around Dallas. He failed to make the cut in qualifying for Byron Nelson in 2008. In February 2018, it was announced that he had received a sponsor’s exemption to play in the PGA Tour’s Corales Puntacana Resort and Club Championship in Punta Cana, Dominican Republic from March 22–25. Romo missed the cut with scores of 77 and 82, dead last in the 132-man field after the second round. In July 2018, he won the American Century Championship, a celebrity tournament.

During homecoming weekend on October 17, 2009, Eastern Illinois University retired Romo’s No. 17 jersey and inducted him into EIU’s Hall of Fame. Romo is the first Eastern Illinois player to have his number retired. He said of the event, “It was such an honor to be inducted into the Hall of Fame here, and with the jersey ceremony, it holds a special place in your heart.”

During the October 25, 2010, Monday Night Football game against the New York Giants, Romo suffered a broken left clavicle. The injury occurred during the second quarter, when Romo was driven to the turf by Giants linebacker Michael Boley. He was placed on Injured Reserve on December 21, 2010, and replaced by veteran Jon Kitna.

Romo’s 102.5 quarterback rating in 2011 was fourth best in the league behind Aaron Rodgers, Drew Brees and Tom Brady, and second highest in Cowboys history.

Romo had four fourth-quarter comebacks in 2011 and had a would-be game-winning field goal attempt missed against the Arizona Cardinals and a would-be game-tying field goal attempt against the New York Giants blocked (the Cowboys lost both of those games).

Romo accounted for 32 of the 39 total touchdowns the Cowboys scored in the 2011 NFL season (82.1%). No other player in the 2011 regular season contributed a higher percentage of team touchdowns (Cam Newton with 72.9% was second).

On May 28, 2011, Romo married Candice Crawford, the 2008 Miss Missouri USA, a former journalist for Dallas television station KDAF, and the sister of actor Chace Crawford. They had dated since the summer of 2009, and became engaged on December 16, 2010. The couple have three sons together: Hawkins Crawford Romo (born April 9, 2012) Rivers Romo (born March 18, 2014) and Jones McCoy Romo (born August 23, 2017).

Romo underwent back surgery on December 27, 2013, and was placed on the Cowboys’ injured reserve list. Garrett announced that Kyle Orton as the starting quarterback for the Week 17 game against the Philadelphia Eagles, which the team lost 24–22, to miss the playoffs for a fourth straight year.

As of 2013, Romo hosted a youth football camp in Burlington, Wisconsin, annually during the summer, since 2004. In the Dallas area, Romo participated in community activities in collaboration with United Way, the Make-A-Wish Foundation, and the Society for the Prevention of Cruelty to Animals.

Romo started strong in the 2015 season, throwing a game-winning pass to Jason Witten with seven seconds left in the Cowboys’ season opener against the New York Giants. He continued to show success in a week 2 victory over the Philadelphia Eagles, but suffered a broken left collarbone in the third quarter after being sacked by linebacker Jordan Hicks. The injury sidelined Romo for eight weeks, during which the Cowboys failed to win a single game with Brandon Weeden and then Matt Cassel starting at quarterback.

Romo was unable to start in the 2016 regular season after suffering a compression fracture to the L1 vertebra in his back during the Cowboys’ third preseason game against the Seattle Seahawks. The injury caused him to miss the first 10 games of the season, with the duties of the team’s starting quarterback being assumed by rookie Dak Prescott.

Although Cowboys owner Jerry Jones initially said Romo would remain the team’s starter when he returned, Prescott’s success with the team and the length of Romo’s injury led to Jones reconsidering his decision. Amid Prescott guiding the team to an eight-game winning streak, Romo conceded his role as starting quarterback to Prescott and began serving as the Cowboys’ backup when he returned to the active roster in Week 11. Romo made his season debut in the regular season finale on January 1, 2017, against the Philadelphia Eagles. In what would prove to be the final play of his career, he threw a touchdown pass to Terrance Williams before Mark Sanchez played the rest of the game.

On April 4, 2017, Romo announced his retirement from the NFL. After announcing his retirement, he was released by the Cowboys, per his request. Following his retirement, Dallas Mavericks owner Mark Cuban announced that Romo would be a “Maverick for a day” for the Mavericks’ final home game of their 2016–17 season. He warmed up with the team and sat in full uniform on the bench, but did not play in the game and was not considered an official member of the roster.

Once the 2017 NFL season got underway, Romo received critical praise for his work as a recent ex-player, most notably for his ability to predict offensive plays and read defensive formations from the booth, and “adding an enthusiasm that had been lacking with Simms.”

In February 2020, Romo renewed his contract with CBS through at least 2022, with the network reportedly paying him $17 million per-year—which would make Romo one of the highest-paid personnel in sports broadcasting and “the highest-paid NFL analyst in television history.”