[2] Fitzpatrick played college football for the Harvard Crimson, where he was the school's first quarterback to have over 1,000 rushing yards, and was selected by the St. Louis Rams in the seventh round of the 2005 NFL draft.

[6] In 2004, Fitzpatrick was named the Ivy League Player of the Year and winner of the George H. "Bulger" Lowe Award, as he accumulated 1,986 yards with 13 touchdowns and six interceptions.

The only player to earn a verified perfect score on the Wonderlic was also a Harvard graduate: wide receiver/punter Pat McInally, who played his entire career for the Cincinnati Bengals.

Head coach Mike Martz named Fitzpatrick the third-string quarterback on the depth chart to begin his rookie season, behind Marc Bulger and Jamie Martin.

On November 27, 2005, Fitzpatrick made his professional regular season debut after entering the game in the second quarter against the Houston Texans to replace injured veteran journeyman Jamie Martin.

Fitzpatrick completed 19 of 30 passes for 310 yards and three touchdowns for a 117.4 quarterback rating and led the Rams from a 24–3 halftime deficit to a 33–27 overtime road victory.

[20] Fitzpatrick was replaced by Martin after halftime the following week, after struggling in a home game against the Philadelphia Eagles in which he completed just 41.7% of his passes for a total of 69 yards.

[36] During a Week 11 49–31 comeback road victory over the Cincinnati Bengals, Fitzpatrick threw for 316 yards and four touchdowns, including three to Stevie Johnson, and two interceptions.

[39] During a Week 2 comeback 38–35 victory over the Oakland Raiders, Fitzpatrick led the Bills to touchdown drives on five straight possessions in the second half.

[47] During a Week 4 38–13 victory over the New York Jets, Fitzpatrick made his Titans debut, replacing an injured Jake Locker in the third quarter.

Following an incident in the locker room, in which starting quarterback Geno Smith suffered a broken jaw after being punched by linebacker IK Enemkpali, Fitzpatrick was tentatively named the Week 1 starter for the Jets.

[61] In the next game against the Indianapolis Colts on Monday Night Football, he threw for 244 yards, two touchdowns, and an interception as the Jets won on the road by a score of 20–7.

[66] During the first quarter of a Week 8 34–20 loss to the Oakland Raiders, Fitzpatrick suffered torn ligaments in his left thumb while scrambling and did not play for the remainder of the game, being relieved by Geno Smith.

[78] In the regular-season finale against the Bills, Fitzpatrick threw for 181 yards, two touchdowns, and three costly interceptions (all in the fourth quarter) as the Jets lost on the road by a score of 22–17 and were eliminated from playoff contention after the Pittsburgh Steelers defeated the Cleveland Browns, despite finishing the year with a 10–6 record.

[83] In the next game on Thursday Night Football against the Buffalo Bills, he improved gradually with 374 passing yards and a touchdown, leading the Jets to a 37–31 victory to earn AFC Offensive Player of the Week.

[89][90] Fitzpatrick then started the team's next two games against the Cleveland Browns and Miami Dolphins before sitting out against the Los Angeles Rams due to injury.

[97] Due to Petty's injury, Fitzpatrick started in the regular season finale, completing 20 of 30 passes for 210 yards and two touchdowns as the Jets beat the Bills by a score of 30–10.

[101][102][103][104] During a Week 6 38–33 road loss to the Arizona Cardinals, Fitzpatrick entered the game after starter Jameis Winston suffered a shoulder injury in the second quarter.

[105] Three weeks later against the New Orleans Saints, Fitzpatrick entered the game after Winston suffered another shoulder injury, completing eight of 15 passes for 68 yards and a touchdown in the 30–10 road loss.

[112] Starter Jameis Winston was handed a three-game suspension, making Fitzpatrick the Buccaneers' starting quarterback to begin the season.

[114] In the next game against the Philadelphia Eagles, Fitzpatrick completed 27 of 33 passes for 402 yards and four touchdowns, finishing with a 144.4 QB rating despite an interception (which was after a juggle his receiver made) as the Buccaneers won by a score of 27–21.

The following week against the Pittsburgh Steelers on Monday Night Football, Fitzpatrick finished with 411 passing yards, three touchdowns, and three interceptions as the Buccaneers narrowly lost by a score of 30–27.

[122] The following week against the Washington Redskins, Fitzpatrick had his fourth 400-yard passing game of the season, throwing for 406 yards and two interceptions, which tied Dan Marino and Peyton Manning for the single-season record as the Buccaneers lost by a score of 16–3.

[123] During a narrow Week 11 38–35 road loss to the New York Giants, Fitzpatrick was benched for Winston again in the second half after throwing for 167 yards and three interceptions in what would be his final appearance of the 2018 season.

He also played against Tom Brady in his final regular season game as a Patriot, as he would sign with the Tampa Bay Buccaneers in the offseason.

[141] On September 7, 2020, Fitzpatrick was confirmed to have won the Dolphins starting job for the second year in a row after beating out rookie quarterback Tua Tagovailoa in training camp.

[152] During a narrow Week 16 26–25 road victory over the Las Vegas Raiders, Fitzpatrick was brought in to relieve Tagovailoa early in the fourth quarter after the latter was benched.

Fitzpatrick led a game-winning drive where he found Mack Hollins for a 34-yard completion down while having his face mask pulled with 19 seconds left in the game and down 25–23 with no timeouts.

[155] Without Fitzpatrick available, the Dolphins lost their Week 17 rematch with the Bills on the road by a score of 56–26 with Tagovailoa at quarterback and were eliminated from postseason contention when the Indianapolis Colts won later that day.

[159] Fitzpatrick started in the season-opening 20–16 loss to the Los Angeles Chargers but suffered a hip subluxation during the second quarter, which resulted in him being placed on injured reserve and missing the rest of the season.