Casilla picked up his first career base hit, a bases loaded, two out RBI ground ball single between Diamondbacks first baseman Paul Goldschmidt and Aaron Hill on September 14, 2012. Casilla was the winning pitcher in Game 4 of the 2012 World Series as the Giants swept the Detroit Tigers.
On December 17, 2012, Casilla re-signed with the Giants for 3 years at $15 million. On May 28, 2013, Casilla underwent knee surgery to remove a cyst and was placed on the 15-day DL.