Mercilus attended the University of Illinois, where he played for coach Ron Zook's Illinois Fighting Illini football team from 2009 to 2011. He broke out during his junior season in 2011, leading the country in quarterback sacks (16) and forced fumbles (9) while primarily playing defensive end. At the conclusion of the 2011 season, Mercilus was a first-team All-Big Ten selection by both the coaches and media. He won the 2011 Ted Hendricks Award, 2011 Bill Willis Award, and 2011 CFPA Defensive Performer of the Year, in addition to being recognized as a unanimous first-team All-American.
Mercilus entered the 2012 NFL Draft where he was drafted by the Houston Texans with the 26th overall pick. He was the highest selected Illinois defensive lineman since Simeon Rice in 1996. Mercilus is expected to transition into a 3–4 outside linebacker for defensive coordinator Wade Phillips.
On June 14, 2012, Mercilus and the Texans agreed to a four-year, $7.634 million contract with a team option for a fifth year.
Through the first six games of the season, Mercilus mostly saw work on special teams. In week 7 against the Baltimore Ravens, Mercilus was used more on defense in a rotation with starting outside linebackers Connor Barwin and Brooks Reed. In the game, Mercilus recorded his first career sack against Joe Flacco, also forcing a fumble on the play. He also tipped a pass leading to an interception.