As a junior in 2006, Jefferson guided Destrehan to an undefeated 6–0 start before suffering a broken wrist after slamming it into the helmet of another player. Jefferson completed 81 of 143 (56.6%) passes for 1,666 yards, 20 touchdowns, and 4 interceptions. Jefferson had a passer rating of 195.1.

As a senior in 2007, Jefferson helped Destrehan High School clinch the Class 5A state championship, finishing with a 15–0 record. He completed 188 of 290 (64.8%) passes for 2,846 yards, 24 touchdowns, and only 3 interceptions during Destrehan’s championship season. Jefferson had a passer rating of 172.5. Jefferson was the Class 5A Offensive Player of the Year, and he was named to the Class 5A All-State first team.

As a true freshman in 2008, Jefferson appeared in seven games, starting two of them including the 2008 Chick-fil-A Bowl of which he was the offensive MVP in a 38–3 win over Georgia Tech.

As a sophomore in 2009, Jefferson was the youngest starting quarterback in the SEC and the youngest to start a season-opener for LSU since Y. A. Tittle in 1945. He started 12 of LSU’s 13 games, missing the game against Louisiana Tech due to injury. He was 8–4 as a starter, throwing for 2,166 yards, 17 touchdowns, and 7 interceptions. Jefferson and the LSU Tigers lost the 2010 Capital One Bowl to the Penn State Nittany Lions 19–17.

In the 2010 regular season, Jefferson threw for 1,253 yards, 4 touchdowns, and 9 interceptions while sharing the quarterback duties with Jarrett Lee. He also rushed for 450 yards and 7 touchdowns; both are LSU records for a quarterback. Jefferson led the Tigers to a 10–2 record in the regular season and beat the Texas A&M Aggies in the 2011 Cotton Bowl Classic with a final score of 41–24. In that game, Jefferson threw for 158 yards and 3 touchdowns. He also rushed for 67 yards and 1 touchdown.

Jefferson’s final three regular season games were LSU’s most productive games in 2011 for total yards and yards per play. In all three games, LSU gained over 450 yards; LSU had gained over 450 yards only once in the prior nine games. Jefferson had a perfect game passing against Ole Miss, and he passed for over 200 yards against Arkansas. LSU averaged nearly 10 points more per game and nearly doubled the rushing yards when Jefferson started as QB. Jefferson finished the regular season with a passer rating of 163.5, highest among SEC starting QBs. Of LSU’s final three regular season opponents, one-third of the opponents were ranked in the Top 25 at the end of the season. Arkansas was ranked 3rd. Of LSU’s first eight regular season opponents, only one-fourth of the opponents were ranked. Oregon was ranked 4th, and West Virginia was ranked 17th. Auburn was the only other team to receive a Top 25 vote. Northwestern State is an FCS school.

Jefferson led LSU to a 42–10 win over Georgia in the 2011 SEC Championship Game. In the 2011 BCS National Championship Game, Jefferson struggled against an Alabama defense seeking redemption from a regular season loss against a Jefferson led LSU Tiger team at Alabama’s home field. Although Jefferson completed nearly 65% of his passes, he was ineffective in executing the option and moving the LSU offense.

Jefferson went undrafted in the 2012 NFL Draft, but was invited to try out at the Tampa Bay Buccaneers’ rookie minicamp. The team signed Jefferson to a contract on May 7, 2012, but was waived four days later so that Tampa Bay could have a replacement for Da’Quan Bowers, a projected starter who suffered a probable season-ending injury.

On August 10, 2012, Jefferson signed with the Montreal Alouettes of the Canadian Football League and was assigned to the practice squad. On October 25, 2012, ESPN reported, citing WAFB in Baton Rouge, LA, that Jefferson was arrested and charged with simple possession of marijuana, along with 3 other former LSU football players, including former Heisman Trophy finalist Tyrann Mathieu. On October 30, 2012, Louisiana State Judge Chip Moore revoked Jefferson’s bond in his 2011 simple battery case and ordered him to report to parish prison by 2 p.m. (that day) due to his arrest on a marijuana charge. Jefferson was subsequently released by the Alouettes.

Jefferson was hired as a graduate assistant wide receivers coach by Colorado State in February 2019.