Cain started on Opening Day for the Giants in 2013. He pitched six shutout innings before being removed due to a high pitch count; however, Kershaw threw a shutout, and the Dodgers beat the Giants 4–0. On April 7, Cain threw two no-hit innings before giving up nine runs in the third inning and getting removed from the game, becoming the first Giants to allow nine runs in an inning since Ernie Shore in 1912. The Cardinals beat the Giants 14–3. On August 23 against the Pirates, Cain was hit by Gaby Sánchez's line drive in the pitching arm, and was placed on the 15-day disabled list for the first time in his career. Cain would finish the season with a record of 8–10 in 30 starts. For the first time since 2006, Cain's ERA sat in the 4's, finishing with an exact 4.00 ERA.