He played college football for the Marshall Thundering Herd, twice receiving MAC Most Valuable Player honors, and was selected seventh overall by the Jacksonville Jaguars in the 2003 NFL draft.

Leftwich held a starting role with the Jaguars during his first four seasons and spent the remainder of his career as a backup for the Atlanta Falcons, Pittsburgh Steelers, and Tampa Bay Buccaneers.

He rejoined Arians as the offensive coordinator of the Buccaneers, a position he held from 2019 to 2022, and helped the team win Super Bowl LV.

Leftwich gained recognition after quarterbacking a 64–61 overtime victory over East Carolina in the 2001 GMAC Bowl, in which he competed against future teammate David Garrard.

[2] Because ESPN began broadcasting Mid-American Conference (MAC) games on Tuesdays and Wednesdays—days without other football on television—in 2000, nationwide "MACtion" audiences watched Leftwich's teams.

[7] Leftwich took over as the Jaguars starting quarterback in game four of his rookie year after Mark Brunell was injured in the previous week's matchup against the Indianapolis Colts.

Leftwich entered his fourth NFL season as the Jaguars' starting quarterback, but without veteran wide receiver Jimmy Smith, who suddenly retired in May 2006.

Leftwich led the Jaguars to victories on national television in consecutive weeks against the favored Dallas Cowboys and Pittsburgh Steelers to begin the 2006 season.

[8] Garrard's ineffectiveness prompted Jaguars head coach Jack Del Rio to replace him with backup Quinn Gray.

In February 2007, Del Rio publicly reaffirmed his commitment to Leftwich, formally naming him as the team's starter over Garrard and Gray.

On August 29, Buccaneers head coach Raheem Morris named Leftwich the team's starter for the 2009 regular season.

After spending several games inactive due to an elbow injury, on November 24 Leftwich was placed on injured reserve, ending his 2009 season.

He was expected to be the starter while Ben Roethlisberger served his four-game suspension,[16] but suffered a knee injury during the preseason finale against the Carolina Panthers.

Leftwich was cut from the Steelers on September 18, 2010, in a temporary move to make room for defensive lineman Steve McLendon, who was signed due to an injury to Casey Hampton.

[19] Leftwich was the Steelers backup quarterback for their playoff run and Super Bowl XLV loss to the Green Bay Packers.

On December 31, 2018, Leftwich was fired by the Cardinals, along with head coach Steve Wilks and the team finished 3–13, their worst record since 2000.

On January 8, 2019, Leftwich was hired by the Tampa Bay Buccaneers as their offensive coordinator, reuniting with new head coach Bruce Arians.

[33] After the 2020 regular season, Arians stated that he had delegated the offense to Leftwich, and expressed frustration that the coordinator was not interviewed by other NFL teams for a head coaching position.