Santana sent the solo shot to center field to give the Tribe a 6-5 triumph Monday in Cleveland. The blast had an exit velocity of 105 mph and left the field in 4.5 seconds, according to Statcast.
The Red Sox tied the game on a Xander Bogaerts RBI double in the top of the final frame. Santana came up as the Indians' first batter in the bottom of the same inning. He settled in against Red Sox reliever Marcus Walden.
Santana worked a 2-2 could against the right-handed pitcher, before smacking a Walden slider over the left center field fence. The solo shot came a day after Santana hit a go-ahead grand slam to help the Indians beat the Minnesota Twins 7-3 Sunday in Minneapolis.
The Indians now sit in first place in the American League Central.
Franmil Reyes gave the Tribe a 2-0 lead with a two-run homer in the bottom of the first inning. Andre Benintendi cut the Indians' lead in half with an RBI double in the next inning for the Reed Sox. Jose Ramirez responded with a three-run homer for the Indians in the bottom of the third inning, giving Cleveland a 5-1 advantage.
Red Sox star J.D. Martinez led off the fourth frame with his 28th home run of the season. Brock Holt also plated Mitch Moreland in the inning. Jackie Bradley cut the Indians' lead to one run with a solo homer in the top of the seventh frame. Bogaerts went on to tie the game by plating Mookie Betts on his two-bagger in the top of the ninth inning.
Brad Hand issued an intentional walk to Martinez before getting Benintendi to fly out and end the top of the inning, sending Santana to the plate for the Tribe's game-winning swat.
Santana is now hitting .286 with 26 homers and 71 RBIs on the season. He went 3-for-4 with three runs scored, an RBI and a walk in Monday's win. Ramirez was 2-for-4 with three RBIs, a run scored and a strikeout in the win.
The Indians host the Red Sox at 7:10 p.m. EDT Tuesday in Cleveland.