Hughes received three varsity letters in football while attending Austin High School in Fort Bend County, Texas, where he played running back. As a senior in 2006 Jerry rushed for 1,412 yards and totaled 19 touchdowns to capture First-team All-District 20-5A honors. Hughes also earned First-team All District as a Kick Returner. Hughes also lettered in baseball where he played third base and pitcher.
Considered only a two-star recruit out of high-school by recruiting service Rivals.com, Hughes failed to draw a lot of attention and only received a few scholarship offers. He picked TCU over Iowa State, Arizona State and North Texas.
Once at TCU, Hughes was one of just four true freshmen to play for the Horned Frogs in 2006. He recorded his first career sack in a 31-17 win over Army. He played in all 13 games as sophomore in 2007, and recorded at least one tackle in each of those contests.
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. He led the nation with his 15 sacks. He garnered first-team All-Mountain West Conference (MWC) and MWC Defensive Player of the Year honors, and was recognized as a consensus first-team All-American.
In 2009 Hughes had a career-high 54 tackles and 11.5 sacks (tied for 7th in NCAA). That season, the Horned Frogs ranked first in total defense, allowing just 233 yards per game and were sixth in the nation with 12.4 points allowed per game. He was a first-team All-Mountain West selection again, and was recognized as a unanimous first-team All-American. Additionally he was named the MWC Defensive Player of the Year for the second time in two years.
His career totals now include 28.5 sacks, 139 total tackles, 39 tackles-for-loss and seven forced fumbles. Hughes earned his bachelor's degree in communications from TCU in 2010.
Consensus first-team All-American – Football Writers Association of America, The Sporting News, Walter Camp Football Foundation, CBS Sports, College Football News, ESPN, Rivals.com, and Sports Illustrated (2008)
Unanimous first-team All-American – Associated Press, American Football Coaches Association, Football Writers Association of America, The Sporting News, Walter Camp Football Foundation, CBS Sports (2009)
During his rookie season of 2010, Hughes appeared in 12 games making 6 tackles.
In 2011, Hughes appeared in 12 games (started 1) making 13 tackles and 1 sack.
On November 16, 2012, Hughes was fined $21,000 for a late hit against the Jacksonville Jaguars in Week 10. He finished the 2012 season by appearing in all 16 games (started 6) with 32 tackles, 1 pass defended, and 4 sacks.
On April 29, 2013, the Colts traded Hughes to the Buffalo Bills for linebacker Kelvin Sheppard. Hughes finished his first season with the Bills by making 46 tackles, 10 sacks and 2 forced fumbles in 16 games (started 1). He was also named to the USA Today All-Joe Team.
On March 9, 2015, the Buffalo Bills and Hughes agreed to a 5-year contract worth at least $45M. That same year, NFL changed the jersey numbering rules, and allowed defensive linemen to wear numbers 55-59, on par with linebackers.