Leftwich has also played for the Atlanta Falcons and Tampa Bay Buccaneers. He earned a Super Bowl ring with the Steelers in Super Bowl XLIII.

Leftwich attended H.D. Woodson High School in Washington, D.C. and was a letterman in football, basketball, and baseball. He garnered an honorable mention on the Washington Post's All-Met football team in 1997 as a senior. He was also first team All-DCIAA East in basketball his senior year.

Leftwich starred at Marshall University in West Virginia. He gained recognition after quarterbacking a 64–61 overtime victory over East Carolina University in the 2001 GMAC Bowl (in which he took on future teammate David Garrard). He is also remembered for being carried by linemen Steve Sciullo and Steve Perretta, after breaking his shin and returning to the game, down the field on multiple series as he rallied his team to a 17 point comeback against Akron in November 2002 (although still lost 34-20. Leftwich, along with fellow Marshall alumni Chad Pennington and Randy Moss is also credited for helping the Mid-American Conference (MAC) gain more national attention (Marshall has since joined Conference USA).

He was the MVP of the 2000 Motor City Bowl.

Leftwich, for his career at Marshall completed 939 of 1,442 passes (65.1 percent) for 11,903 yards, 89 touchdowns and only 28 interceptions. He amassed 12,090 yards of total offense on 1,632 plays, ranking second on the school’s all-time record lists behind Chad Pennington.

At the 2003 NFL Draft, the Minnesota Vikings and Baltimore Ravens agreed to a trade to move the Ravens into position to take Leftwich with Minnesota's seventh overall selection. However, one of the teams had second thoughts at the last minute and the Vikings missed the allotted time for their pick. As a result, they defaulted the selection and were dropped to ninth. The Jaguars, originally supposed to draft eighth, moved up and took Leftwich with the seventh overall pick.

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.

For the first 11 games of the 2005 regular season, Leftwich was developing into the quarterback the Jaguars believed he would become when they picked him in the first round of the 2003 NFL Draft. He obtained a passer rating of 89.3, ninth-best in the NFL, and a 3:1 touchdown:interception ratio (15:5).

However in the regular season against the Arizona Cardinals, Leftwich suffered a broken ankle after being sacked by Cardinals' safety Adrian Wilson on the first play of the game. Leftwich missed the remaining five games of the regular season. He returned against the New England Patriots in the AFC Wild Card round of the playoffs. The Patriots won 28–3.

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. Leftwich suffered an ankle injury in a week 4 loss to the Washington Redskins. Following a week 6 loss to the Houston Texans, Leftwich had surgery to repair the ankle, which effectively ended his season.