He was selected by the Indianapolis Colts in the first round (30th overall pick) of the 2006 NFL draft out of Louisiana State University.

He played for the team for six seasons where he won Super Bowl XLI, defeating the Chicago Bears.

[2] During his tenure with the Louisiana State University Tigers, he ranked fifth all-time in rushing, with 2,577 yards, despite being primarily used as a blocking fullback early in his career.

His first big game came against the University of South Carolina, during which he gained 98 yards on eleven carries and scored two touchdowns.

On November 9, 2002, he amassed 91 yards, including a 63-yard run for a score, against the Kentucky Wildcats at Commonwealth Stadium.

His performance helped to set the stage for The Bluegrass Miracle, a "miraculous" 74-yard game-winning touchdown pass from quarterback Marcus Randall to wide receiver Devery Henderson as time expired on the last play of the game.

Addai ranked second to freshman Justin Vincent in rushing, gaining 520 yards on 114 attempts.

The following week, he teamed with Alley Broussard (250 yards on 26 carries) to lead the Tigers to a 27–24 victory over the Ole Miss Rebels.

During his senior season, Addai led the team with 911 rushing yards on 187 carries, scoring nine touchdowns.

[7] On November 26, 2006, Addai tied a Colts franchise record for most rushing touchdowns in a game held by Lenny Moore, Lydell Mitchell, and Eric Dickerson, as well as the NFL rookie record by rushing for 4 touchdowns against the Philadelphia Eagles.

[12] On January 21, 2007, in the AFC Championship Game against the New England Patriots, Addai scored the game-winning touchdown with 1:00 remaining, giving the Colts a victory and a trip to Super Bowl XLI.

[15] On November 1, 2009, in a game against the San Francisco 49ers, Addai completed his first professional pass, a touchdown to Reggie Wayne.