On September 22, 2008, Santana pitched against the Seattle Mariners, going 8 innings, allowing 5 hits, 1 earned run, and striking out 9 en route to his career-high tying 16th win of the season. He finished the season with a career-high 214 strikeouts, good for second in the American League behind A.J. Burnett, while pitching to a 3.49 ERA in 219 innings across 32 starts. On October 3, he gave up 4 runs in the first inning and 5 total in 5 1/3 innings against the Boston Red Sox in Game 2 of the ALDS. He finished tied for sixth in the voting for the American League Cy Young Award with Mike Mussina.