He played college football for the TCU Horned Frogs, where he was twice recognized as a consensus All-American before being selected by the Indianapolis Colts in the first round of the 2010 NFL draft.

Hughes received three varsity letters in football while attending Austin High School in Fort Bend County, Texas, where he played running back.

Hughes accepted an athletic scholarship to attend Texas Christian University, and played for coach Gary Patterson's TCU Horned Frogs football team from 2006 to 2009.

Patterson recognized Hughes' natural athleticism and assigned him jersey number 98, usually reserved for defensive linemen.

Taking over as a full-time starter as a junior in 2008, Hughes recorded 15 sacks, 18.5 tackles for a loss, 6 forced fumbles, 2 interceptions and returned one of those picks for a touchdown.

[11] Hughes finished his first season with the Bills by making 46 tackles, 10 sacks and two forced fumbles in 16 games with one start.

[17] In the AFC wild card game against the Houston Texans, Hughes sacked quarterback Deshaun Watson 3 times during the 22–19 overtime loss.

In Week 15 against the Denver Broncos, Hughes recovered a fumble forced by teammate Tre'Davious White on Drew Lock and returned it for a 21 yard touchdown during the 48–19 win.

[19] In the Divisional Round of the playoffs against the Baltimore Ravens, Hughes recorded two sacks on Lamar Jackson during the 17–3 win.

[22] A free agent after the season, he finished his 9-year tenure with Buffalo having amassed 53 sacks, ranking 4th in team history at the time.