In 2003, LeFors became the starting quarterback for the Louisville Cardinals football team. In 2004, LeFors started every game that season. LeFors ranks as the 4th all time leading passer at the University of Louisville with 5,853 yards & first in pass completion percentage with 66%. In 2004, he narrowly missed breaking Daunte Culpepper's season-record completion percentage with 73.5 to Culpepper's 73.6. He led Louisville that season to an 11-1 season in which they finished 6th in the final AP Poll (the highest finish in school history) and won the Liberty Bowl. Louisville was the only D-1A (now FBS) university to recruit LeFors out of high school as a quarterback. LeFors was redshirted as a freshman in 2000 and served as a backup to Dave Ragone in 2001 and 2002. In 2003 he took over as a starter, throwing for 3,145 passing yards and 17 touchdowns, and was named 1st team All-Conference USA Quarterback in both 2003 and 2004. He was also named Conference Player of the Year in 2004 and named a finalist for the Johnny Unitas Golden Arm Award as a senior. LeFors participated in the East West Shrine Game (college all-stars) and was named Offensive Player of the Game.
LeFors was selected by the Carolina Panthers in the fourth round (121st overall pick) of the 2005 NFL Draft out of the University of Louisville. After serving one season in a backup role, he was released by the Panthers in September 2006. LeFors conducted workouts for the Tampa Bay Buccaneers, Minnesota Vikings, Seattle Seahawks, Buffalo Bills, Detroit Lions, Oakland Raiders, and Denver Broncos but was not offered a contract. In December 2006, LeFors was signed by the Edmonton Eskimos of the CFL as an import player. He was the backup quarterback for the team's 2007 season, but had the opportunity to start 5 games at the end of the season because of Ricky Ray's shoulder injury. By the end of the 2007 CFL regular season, Lefors was placed 8th in the league in passing yardage with 1193 yards, as well as 6 TDs and 8 INTs, while completing 60.8% of his passes. He was 7th in QB rushing yardage with 204 yards and 2 TDs. His best performance of the season came in week 18 against Saskatchewan. In a losing effort, he managed to complete 34/48 passes for 412 yards 3 TDs and 1 INT, while scrambling 6 times for 31 yards. According to head coach Danny Maciocia, Lefors shares the job as 2nd string QB on the Eskimo depth chart for the 2008 campaign with Jason Maas. He has also been given the role of field goal holder for kicker Noel Prefontaine, as Lefors is left-handed and Prefontaine kicks with his left foot.
On January 21, 2009, Stefan LeFors was traded to the Winnipeg Blue Bombers for a second-round pick in the 2009 CFL draft and a conditional selection in 2010. Then on June 18, 2009 Stefan was named Winnipeg's starting quarterback for the start of the 2009 season. In the offseason preceding the 2010 CFL season he was released by the Bombers.
LeFors returned to Louisville after he was waived by the Bombers and took a position with the U of L athletic department, also serving as a color analyst for the U of L radio network during the 2010 football season. In May 2011, he was named as the new head coach of the high school team of the Christian Academy of Louisville, and left the U of L athletic department effective with the 2011–12 school year.