In 2012, during organized team activities (OTAs), Melton appeared in the backfield as a running back, resembling former Bears defensive lineman and fullback William Perry; Melton had not played running back since his days at Texas. In the season opener against the Indianapolis Colts, Melton sacked Andrew Luck twice as the Bears went on to win 41–21. On December 26, Melton was named to his first Pro Bowl. In the 2012 season, Melton recorded 32 tackles and six sacks, tied for third in the league among defensive tackles. On March 1, 2013, Melton was given the franchise tag by the Bears, worth $8.45 million.