In the playoffs, McNabb led the Eagles to their second Super Bowl trip ever, with victories over the Minnesota Vikings 27-14 and Atlanta Falcons 27-10 for the NFC Championship. Owens was not in the lineup during the two playoff victories, and was recovering from a broken ankle. McNabb became only the third African-American quarterback to start in a Super Bowl after Doug Williams in the 1987 season and Steve McNair in 1999.

After redshirting in 1994, his first year at Syracuse, McNabb went on to start every game during his college career, compiling a 35–14 record. As a freshman, he completed the longest touchdown pass in Syracuse’s history—a 96-yard throw against West Virginia University—in a game where he accounted for 354 total yards of offense; he was named the Big East Conference’s rookie of the year at the end of the season. McNabb amassed 2,892 yards of total offense in his junior season to set a school record. As a senior, he led Syracuse to a berth in the Orange Bowl against Florida, as he completed 157 of 251 passes (62.5%) for 2,134 yards; he also pushed the eventual champions, the 1998 Tennessee Volunteers, to the limit in a very close game. His 22 touchdown passes tied the school’s single-season record, set by former Eagle Don McPherson in 1987. McNabb also rushed 135 times for 438 yards and eight touchdowns. He ranked sixth in the nation with a 158.9 passing efficiency rating and 22nd in total offense, with 233.8 yards per game. He tied a school record with four touchdown passes against Cincinnati, and scored five touchdowns against Miami (three rushing and two passing). McNabb was also teammates with future NFL star Marvin Harrison for one season at Syracuse.

McNabb also played basketball at Syracuse University as a reserve guard. In the 1996 NCAA Men’s Division I Basketball Tournament national championship game against the University of Kentucky Wildcats, McNabb played against his former high-school teammate Antoine Walker.

McNabb was drafted in the first round with the second overall pick by the Eagles, behind first pick Tim Couch, in the 1999 NFL Draft. McNabb was the second of five quarterbacks selected in the first 12 picks of a quarterback-rich class that was at that point considered the best quarterback draft since the famous class of 1983. However, only McNabb and Daunte Culpepper went on to have successful careers in the NFL; Tim Couch struggled with the Cleveland Browns and officially retired in 2007 after being cut by the Jacksonville Jaguars in a failed comeback bid, while Akili Smith and Cade McNown were out of the NFL by 2002. By 2006, only McNabb was still with the team that originally drafted him.

McNabb threw the first touchdown pass of his career (six yards to tight end Chad Lewis) vs. Indianapolis in a 44-17 home loss on November 21, 1999. McNabb went on to start six of the Eagles’ final seven contests (missing the December 19 home game against New England, a 24-9 victory, due to injury).

In his first full season as an NFL starter in 2000, McNabb finished second in the Associated Press MVP voting (24-11) to St. Louis Rams running back Marshall Faulk, who set the NFL record for most touchdowns scored in a season. McNabb made his primetime debut on ESPN against Atlanta at home on October 1, with his first 300-yard passing game in a 38-10 victory and the Eagles’ first 300-yard passer since Bobby Hoying against the Cincinnati Bengals at home on November 30, 1997. McNabb’s 55 pass attempts at Pittsburgh in a come-from-behind 26-23 overtime victory on November 12 were a career high and the fourth-highest total in team history. He was named the NFC Offensive Player of the Week after accounting for 90.7% of the offense in a 23–20 victory at Washington on November 26. His 125 rushing yards were the most by an NFL quarterback since the Chicago Bears’ Bobby Douglass rushed for 127 on December 17, 1972, and was the sixth-best rushing effort by a quarterback since 1940 when the T formation was introduced. He threw for a career-high 390 passing yards and four touchdowns in a 35-24 victory at Cleveland on December 10 en route to NFC Offensive Player of the Week honors. McNabb led the Eagles to their first playoff appearance since 1996, where they defeated the favored Tampa Bay Buccaneers 21–3 before losing to the New York Giants 20–10.

McNabb was selected as a first alternate to the NFC Pro Bowl squad in 2000 (behind Daunte Culpepper, Jeff Garcia, and Kurt Warner). When Warner was unable to participate due to injury, McNabb took his spot and led the NFC on a touchdown-scoring drive in his first series. He accounted for 74.6% of the team’s total net yards in 2000. Only Carolina’s Steve Beuerlein (75.3%) and San Francisco’s Garcia (75.1%) had a higher percentage. His 629 rushing yards in 2000 led the Eagles, was the highest among NFL quarterbacks, and at the time was the fourth-highest total ever (968 by Bobby Douglass in 1972, 942 by Randall Cunningham in 1990, and 674 by Steve McNair in 1997). Michael Vick has since eclipsed that total three times). His six rushing touchdowns in 2000 were the most by an Eagles quarterback since Randall Cunningham, who also had six in 1988. McNabb broke the club’s single-season record for most attempts (569) and completions (330) in 2000, marks previously set by Cunningham (560 and 301, respectively) in 1988. He was named 2000 NFL Player of the Year by CBS Radio and the Terry (Bradshaw) Awards on Fox Sports and was named to the All-Madden team.

McNabb earned his second trip to the Pro Bowl (was originally elected as an alternate) following the 2001 season after combining for 3,715 yards of total offense and establishing career highs in touchdown passes (25) and quarterback rating (84.3). Including playoffs, he threw touchdown passes in 15 of 18 games and two-or-more in 12 of those games. He was named by his teammates as the club’s offensive MVP in 2000 and 2001. During the off season, McNabb signed a new contract with the Eagles worth $115 million over 12 years, with a $20.5 million signing bonus.

McNabb led the Eagles in fourth-quarter comebacks in two wins vs. the Giants in 2001. At the Meadowlands on October 22, his 18-yard pass to James Thrash with 1:52 remaining gave the Eagles a 10-9 victory. He wiped out a 21-14 deficit on December 30, engineering two fourth-quarter scores as the Eagles clinched the NFC East title with a 24-21 over archrival Giants. His eight career playoff touchdowns trail only Ron Jaworski (9). He was named NFL Offensive Player of the Week after the NFC Divisional Playoff game at Chicago on January 19, 2002, completing 26-of-40 for 262 yards and two touchdowns passing and adding 37 yards and a touchdown on the ground, which was also the final touchdown at the old Soldier Field. He became only the fourth quarterback in Eagles history to pass for 3,000 yards in consecutive seasons – Sonny Jurgensen (1961–62), Ron Jaworski (1980–81), and Randall Cunningham (1988–90) were the others. McNabb’s Eagles advanced to the NFC championship game for the first time since 1980, losing to the heavily favored St. Louis Rams.

In 2002, McNabb, who holds a bachelor of science degree in speech communication from Syracuse University, was named to the institution’s board of trustees; he is one of the youngest trustees to have served there. McNabb currently is an athlete partner and serves on the advisory board for MODe Sports Nutrition.

Despite the slow beginning in the 2003 season, McNabb again led his team to the NFC championship game. Although the slow start hindered his overall statistics for 2003, McNabb had the highest quarterback rating (97.5) in the NFL for the second half of the season and also completed over 62% of his passes for over eight yards per attempt. With Philadelphia’s 14–3 home loss to the underdog Carolina Panthers in the 2003 NFC championship game, McNabb became the first NFL quarterback since Danny White of the Dallas Cowboys (1980–1982) to lead a team to three consecutive defeats in conference title games, prompting some observers to conclude that McNabb “chokes” in big games (his cumulative passer rating in the three conference championship games was 50.5 – a figure about 10 points lower than what the worst quarterback in the league earns over the course of a typical year). McNabb was knocked out of the NFC title game after being hit on the ground by Panthers’ linebacker Greg Favors after he had been tripped up on a broken play.

McNabb’s success during this period came despite the Eagles having arguably the two worst starting wide receivers in the NFL. In 2003, Philadelphia’s wide receivers caught only five touchdown passes, tying the record for fewest in a 16-game season. By going the entire months of September and October without having a wide receiver catch a touchdown pass, the 2003 Eagles became the first NFL team since 1945 not to have gotten a touchdown pass from any of its wide receivers in the first two months of a season.

McNabb married his college sweetheart, Raquel Ann Sarah “Roxie” Nurse, in June 2003. They have four children: daughter Alexis, who was born in September 23, 2004, twins Sariah and Donovan Jr., who were born in 2008, and Devin James, who was born in 2009. The family splits its time between homes in Moorestown, New Jersey and Chandler, Arizona.

McNabb’s 2005 season began with turmoil and ended on the injured reserve list. While not speaking with his main target, Terrell Owens, and all the distractions that came with the Owens controversy, McNabb was named the NFC’s Player of the Month for September. That month, McNabb threw for 964 yards, eight touchdowns, and only two interceptions in three games, leading the Eagles to a 2-1 record. McNabb carried that momentum into October as he went 33-for-48 (68.8% completions), and threw for 369 yards and three touchdowns en route to leading the Eagles to a memorable come-from-behind victory at an unfriendly Arrowhead Stadium against the Kansas City Chiefs. McNabb could not keep the momentum rolling, however, as the Eagles lost four straight games. Over that span, McNabb posted a quarterback rating higher than 72 only once, on November 6, at the Washington Redskins. After playing with a sports hernia and sore thumb, McNabb’s season was finally over after a disastrous effort at home on November 14 on Monday night against the rival Dallas Cowboys. McNabb was intercepted by Roy Williams towards the end of the game, and tried to tackle the defender when Scott Shanle came in and tackled McNabb to the ground. McNabb had injured his groin on the play and was placed on the injured-reserve list later that week. Mike McMahon replaced him at quarterback, and went 2–5 as a starter, with the Eagles finishing the season with a 6–10 record overall. Though low for his standards, McNabb put up respectable numbers in 2005. In nine games, he threw for 2,507 yards, 16 touchdowns, and 9 interceptions. To go along with that, he completed 59.1% (211-357) of his passes. Prior to his season-ending injury, McNabb was on pace to throw for 4,457 yards, which would have easily eclipsed his career high of 3,875, set in 2004.

In October 2007 he wrote a song for Adrian College and it debuted in a game against Olivet College.

On January 11, 2009, McNabb led the Eagles past the Giants in the divisional round of the playoffs. The Eagles won 23–11 and advanced to the NFC Championship game against the Arizona Cardinals, whom they had beaten earlier in the season. In the game, McNabb was penalized for unsportsmanlike conduct, when after being tackled into the Giants’ sideline after a lengthy run, he picked up the Giants’ coaching phone in jest.

In the 2009 NFL Draft, the Eagles picked Missouri Tigers star wide receiver Jeremy Maclin to add to McNabb’s receiving corps, with Kevin Curtis and DeSean Jackson. While Curtis only caught 77 yards, Maclin had 773 yards and four touchdowns in a respectable rookie season, while Desean Jackson had his first 1,000-yard season. Another reliable target for McNabb was the new starting tight end Brent Celek, with whom he connected 76 times for 971 yards and eight touchdowns.

McNabb reached 200 career touchdowns and 30,000 career yards passed in a win against the Washington Redskins on October 26, 2009, with a 45-yard touchdown pass to DeSean Jackson.

The wild card rematch with Dallas proved to be just as disastrous, if not worse. McNabb struggled early on and was unable to get the offense into a rhythm until too late. His lone score came in the second half from a meaningless touchdown to DeSean Jackson. Philadelphia fell 34-14 to Dallas, marking the first time McNabb had ever lost a first-round playoff game. Despite having had arguably one of his best seasons statistically in 2009, McNabb began to face criticism and speculation about his future with the Eagles. McNabb was given Pro Bowl honors for the last time in his career. McNabb was 3 of 10 for 78 yards and one touchdown to DeSean Jackson, while also leading the NFC team in rushing with four carries for 26 yards.

McNabb’s finest moment of the season and of his career came that year in a week-13 game with fellow Super Bowl-contending Green Bay Packers. After starting the game completing his first 14 passes (an NFL record), he led the Eagles to a 47-17 blowout victory. McNabb passed for an Eagles’ record 464 yards and five touchdowns, which all came in the first half. In 2010, it was ranked number one by Eagles fans as the ‘game of the decade.’

In the press conference following the Eagles’ loss to Dallas, and even up to April 1, Andy Reid stated that McNabb would remain the starting quarterback in Philadelphia for the 2010 season. However, on April 4, the Eagles traded McNabb to the Washington Redskins in return for a second-round (37th overall) pick in the 2010 NFL draft and a conditional third- or fourth-round pick in the 2011 NFL draft. The conditional pick became a fourth-round pick in 2011, which was traded to the Tampa Bay Buccaneers in exchange for a lower fourth-round pick in 2011 and a fourth-round pick in 2012. The fourth-round pick in 2012 was then traded, along with a 2012 third-round pick, to the Houston Texans for a lower 2012 third-round pick and linebacker DeMeco Ryans.

In week 8, Shanahan stated in a press conference that McNabb would remain the Redskins’ starting quarterback. On November 15, 2010, McNabb signed a five-year extension worth $78 million ($3.5 million guaranteed) with a chance to make it $88 million by completing incentives. The deal stated that if McNabb was not cut or traded at the conclusion of the 2010 season, he would receive a $10 million bonus. The same day, his Redskins suffered a 59-28 defeat by his former team, the Eagles, at home on Monday Night Football. McNabb finished the game going 17 of 31 for 295 yards with two touchdowns and three interceptions.

On December 17, 2010, head coach Mike Shanahan relegated McNabb to the third quarterback position for the rest of this season, stating that he wanted to evaluate backup Rex Grossman in game play.

On July 27, 2011, the Washington Redskins and the Minnesota Vikings came to an agreement on terms for a trade. After restructuring his contract, Washington traded McNabb to Minnesota in exchange for a sixth-round draft pick in 2012 and a conditional sixth-round draft pick in 2013. McNabb had been rumored as a possible addition to the Vikings for the past three years, in part due to his relationship with then-coach Brad Childress, the former Eagles offensive coordinator. Vikings punter Chris Kluwe agreed to give McNabb his number 5 jersey, in exchange for a $5,000 donation to Kick for a Cure, McNabb to promote Kluwe’s band “Tripping Icarus” during a press conference, and an ice cream cone.

McNabb requested and was granted his release from the team on December 1, 2011, with a reported interest in joining the Houston Texans, Kansas City Chiefs, or his hometown Chicago Bears, all three of which had lost their starting quarterbacks for the season to injury, but were still making playoff pushes. While the Texans and Chiefs had signed Jake Delhomme and Kyle Orton, respectively, prior to McNabb becoming a free agent, the Bears had not signed anyone and expressed interest in adding McNabb. It was ultimately decided that it was too late to add a free-agent quarterback for the playoff hunt, as it would be tough to grasp their offense in the short period of time. The Bears subsequently signed Josh McCown.

In September 2012, McNabb joined the NFL Network as an analyst. In 2013, McNabb became an analyst on Fox Sports Live, Fox Sports 1’s flagship program, and in August 2014, it was announced that McNabb would provide color commentary alongside Dick Stockton for a few games during the 2014 NFL season for Fox. He resigned from Fox in late 2015. In August 2016, McNabb became the lead analyst for beIN Sports college football coverage, and he also joined ESPN Radio as an analyst.

On July 29, 2013, McNabb officially retired from professional football as a member of the Philadelphia Eagles.

McNabb’s nephew, Darnell Nurse, was the seventh overall pick by the Edmonton Oilers in the 2013 NHL Entry Draft.

In April 2014, McNabb served a one-day jail sentence in Maricopa County, Arizona, for a 2013 conviction for driving under the influence (DUI).

On June 28, 2015, McNabb was arrested for DUI following a traffic accident in Gilbert, Arizona. He pleaded guilty and was sentenced to 90 days, 18 to be served in jail and the remainder under house arrest. He was also assessed a $6,000 fine and required to do 30 hours of community service. He paid his fine and began serving his time on November 30, 2015. On December 18, McNabb was released from jail after having served an 18-day sentence, and then completed a 72-day house arrest sentence.

On December 12, 2017, McNabb was suspended by ESPN as the organization investigated allegations of sexual harassment when he worked at NFL Network. In January 2018, McNabb and fellow football analyst Eric Davis were officially fired from the network.