He opted to forgo his senior year and was selected by San Francisco in the fourth round of the 2013 NFL draft.

In 2016, he was named head football coach at Heathwood Hall prep school in Columbia, South Carolina.

On September 11, 2010, in just his second career college football game, Lattimore broke 42 tackles on 37 carries, rushing for 182 yards and two touchdowns against the Georgia Bulldogs.

[4][5] On October 16, 2010, Lattimore scored two touchdowns in a road loss to the Kentucky Wildcats before missing the rest of the game with an ankle injury.

[16] He tore a knee ligament on October 15 against the Mississippi State Bulldogs and it was announced that Lattimore would miss the remainder of the 2011 season due to the injury.

[17] In Lattimore's first game back following his knee ligament injury, he rushed for 110 yards and two touchdowns on 23 carries as the Gamecocks topped Vanderbilt, 17–13.

[20] On October 6, the Gamecocks played host to the Georgia Bulldogs in a top ten showdown for which ESPN College Gameday was in town.

[22] South Carolina football head coach Steve Spurrier stated that Lattimore had dislocated his right knee and torn every ligament, while also suffering nerve damage.

[31] In mid-December 2015, Lattimore announced that he would join the staff of newly appointed South Carolina head coach Will Muschamp.

[32][33] However, in April 2016, the NCAA indicated that the university would gain an unfair recruiting advantage by hiring Lattimore, due to his work with high school kids through his foundation.

[35] On May 6, 2016, it was announced that Lattimore would be joining the football staff at Heathwood Hall Episcopal School in Columbia, South Carolina.

[37] On January 11, 2018, it was announced that Lattimore would be joining Will Muschamp's coaching staff at South Carolina as Director of Player Development.