[2] 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.

As a senior in 2007, Jefferson helped Destrehan High School clinch the Class 5A state championship, finishing with a 15–0 record.

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.

In the 2010 regular season, Jefferson threw for 1,253 yards, 4 touchdowns, and 9 interceptions while sharing the quarterback duties with Jarrett Lee.

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.

Jefferson threw a key pass to running back Stevan Ridley in the LSU game with Alabama on November 6.

Over the course of his first four games back (Kentucky, Florida, Tennessee, and Auburn), Jefferson completed 6 of 10 (60%) passes for 123 yards, 2 touchdowns, and no interceptions for a passer rating of 229.3.

Lee was given another chance on LSU's second possession of the second half, but he immediately threw his second interception of the game which led to an Alabama field goal and lead.

[6] In overtime, Jefferson executed a short-side option to Michael Ford to set up the game-winning field goal.

Jefferson’s ability to run the ball forced opposing defenses to account for him which allowed LSU to defeat opponents through its rushing attack.

Jefferson went undrafted in the 2012 NFL draft, but was invited to try out at the Tampa Bay Buccaneers' rookie minicamp.

[17] The team signed Jefferson to a contract on May 7, 2012,[18] 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.

[19] On August 10, 2012, Jefferson signed with the Montreal Alouettes of the Canadian Football League and was assigned to the practice squad.

[20] On October 25, 2012, ESPN reported, citing WAFB in Baton Rouge, LA, that Jefferson was arrested and charged with simple possession of marijuana,[21] along with 3 other former LSU football players, including former Heisman Trophy finalist Tyrann Mathieu.

[22] 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.

[24] Jefferson signed with the Omaha Mammoths of the Fall Experimental Football League for the 2014 season, where he was the starting quarterback.