In the postseason, Ortiz hit five home runs and 13 RBIs while batting .353 to lead the Red Sox to a World Series championship, the franchise's eighth. In Game 2 of the American League Division Series against the Tampa Bay Rays, he hit two home runs off of Rays' ace pitcher David Price. In Game 2 of the American League Championship Series versus the Detroit Tigers, Ortiz hit a dramatic, game-tying grand slam off reliever Joaquín Benoit in the bottom of the eighth inning, helping propel the Red Sox to victory. In the World Series against the St. Louis Cardinals, Ortiz hit home runs in both Games 1 and 2, had six RBIs and batted .688 as the Red Sox won the series 4-2. He tied a Series record by reaching base nine times in a row, and the opposing Cardinals seemed to stop trying to get him out, with many intentional walks. As a result of his performance, Ortiz was awarded the World Series Most Valuable Player award.
Ortiz gained several new nicknames from the media and his teammates as a result of his great postseason play such as "Señor Octubre" and "Cooperstown." He finished third in Boston's mayoral race that year with 560 write-in votes. He also finished 10th in AL MVP voting, the first season he garnered votes since 2007.