As a freshman at Virginia Tech in 2009, David Wilson played in all 13 games and had 334 rushing yards on 59 carries with four touchdowns. In 2010 he had 619 yards on 113 carries and five touchdowns. He also had 234 yards on 15 receptions with four touchdowns. In 2011 Wilson took over as the Hokies starting running back after Ryan Williams and Darren Evans went on to the NFL. He finished the season with 1,709 rushing yards on 290 carries, and was named the 2011 ACC Offensive Player of the Year.

He was selected in the first round of the 2012 NFL Draft by the New York Giants, 32nd overall. On December 9, 2012, Wilson set the New York Giants team record for all-purpose yards in a single game when he accumulated 327 yards in a win against the New Orleans Saints. Wilson returned four kickoffs for 227 yards (including a 97-yard return for a touchdown) and also ran for 100 yards with two touchdowns on just 13 carries. He became the first player in NFL history with 200 kick return yards and 100 rushing yards, and the second player since 1970 with a kick return touchdown and two rushing touchdowns, in the same game.