On August 31, 2016, the Athletics traded Crisp with cash considerations to the Indians for Colt Hynes. Before he agreed to waive his no-trade clause, Chris Antonetti, the Indians' general manager, spoke with Crisp to tell him that he would not receive enough playing time in Cleveland for his option to vest. In 2016, he batted .208 for Cleveland.
On October 10, 2016, against the Boston Red Sox in Game 3 of the ALDS, Crisp hit a go-ahead two-run home run, which would eventually be the game-winner after the Indians won 4-3. The Indians' win propelled them to the ALCS against the Toronto Blue Jays. It was Crisp's second career postseason home run. However, he and the Cleveland Indians could not hold on in the World Series, losing the Series in Game 7 to the Chicago Cubs.