[2] He started his rookie season as the fifth defensive end on the Colts' depth chart behind Dwight Freeney, Robert Mathis, Eric Foster, and Fili Moala.

On October 30, 2011, Mathews had three tackles and made his first career sack on Matt Hasselbeck, as the Colts lost, 27–10, to the Tennessee Titans and fell to 0–8.

During the 2012 off-season, the Indianapolis Colts fired head coach Jim Caldwell and hired Chuck Pagano in his place.

The next game, he was credited with half a sack and made two combined tackles during the Colts' 23–7 win at the Kansas City Chiefs.

[5] On January 4, 2014, Mathews played in his first career playoff game and made two combined tackles in a 45–44 wild-card victory over the Kansas City Chiefs.

[8] He began the regular season as the fourth defensive end on the Chargers' depth chart behind Kendall Reyes, Corey Liuget, and Tenny Palepoi.

On December 20, 2014, Mathews and Dwight Freeney sacked Colin Kaepernick, forcing a fumble which led to a recovery and touchdown by Corey Liuget.

Mathews finished the 2014 season with career-high stats, recording 1.5 sacks, two forced fumbles, and 21 tackles in 12 games and two starts.

[2] On October 4, 2015, Mathews received his first official start of the season and made one solo tackle in 30–27 victory over the Cleveland Browns.

The following game, he made two combined tackles and sacked Pittsburgh Steelers' quarterback Ben Roethlisberger during the Chargers' 20–24 loss.

[2][9] He started the regular season as the third defensive end on the depth chart behind Cameron Heyward and Stephon Tuitt.