On September 21, 2016, Santana hit his 150th career home run, doing so against the Kansas City Royals. During the regular season, Santana batted .259, 34 home runs, 87 RBI and .865 OPS. He produced 30 home runs and 68 RBI when batting left handed. Santana homered twice in the 2016 American League Championship Series versus the Toronto Blue Jays. He also recorded the final out of the Series by catching a Troy Tulowitzki pop-up in foul territory, sending the Indians to the World Series. The Chicago Cubs defeated Cleveland in the World Series in seven games. The Indians exercised their $12 million option for 2017.