The Giants won the NL West again in 2012. Casilla appeared in all five games of the NLDS against the Cincinnati Reds. In Game 1, he came on with San Francisco trailing in the ninth and allowed two runs, though only one was earned, as the Giants lost 5–2. However, he allowed no runs in the other four games, as San Francisco won the series in five games. In the NLCS against the St. Louis Cardinals, Casilla pitched in his sixth playoff game in a row in Game 1, did not pitch in the next three, and pitched in three straight to finish the series. He did not allow any runs, as San Francisco rallied from a 3–1 deficit to defeat the Cardinals in seven games. Against the Detroit Tigers in Game 2 of the 2012 World Series, Casilla relieved Madison Bumgarner to begin the eighth with the Giants leading 1–0. He threw a scoreless inning, helping preserve a 2–0 victory. In Game 4, he came on with two outs in the ninth and got Gerald Laird to ground out to end the inning, then picked up the win after the Giants scored in the 10th, sweeping the Detroit Tigers to win the series.