Crain was used as the setup man for 2013. From April 17 to June 22, Crain pitched 29 straight scoreless appearances, a franchise record. On July 3, Crain was placed on the disabled list with a right shoulder strain. In 38 games with Chicago, Crain went 2-3 with 19 holds and a 0.74 ERA, striking out 46 in 36.2 innings. Crain was elected to the All-Star Game, but since he was injured, he was replaced by Justin Masterson.