Cleveland Pounds Sox 14-9 [VIDEO]
"We swung the bats very well today. It's a good thing because man, they just kept coming," Cleveland manager Terry Francona said.
Santana was 3 for 4 with five RBIs as Cleveland matched its season best for runs. Greg Allen added a pair of triples and drove in two runs for the Indians, who had a season-high nine extra-base hits.
Jose Ramirez had two doubles and two RBIs and Kevin Plawecki also drove in two runs for the Indians, who won two of three against the World Series champions in Boston.
Mookie Betts, Jackie Bradley Jr., Andrew Benintendi and Xander Bogaerts homered for the Red Sox.
"You don't want to lose these kind of games. But it's just part of it. It's a long season and we've got a long way to go," Betts said. "It's there. It's just a matter of putting it together. You never know when it's going to come."
The Indians, shut out over the first seven innings Tuesday night before rallying with seven runs over the last two for a 7-5 victory, scored at least once in each of the first seven innings Wednesday.
The Red Sox scored three in the eighth, two on Bogaerts' 10th home run of the season, to pull to 14-9. They loaded the bases with one out in the ninth before the Indians called on Brad Hand to close it out for his 15th save.
"It was a tough one all around," Boston manager Alex Cora said. "We put together some good at-bats and we got closer, but it wasn't enough."
Shane Bieber (4-2) got the win despite allowing six runs and eight hits in five innings. He struck out six.
Plawecki's RBI double in the fifth made it 8-6. Ramirez broke it open in the sixth with a two-run double and the Indians added four more in the seventh, two on a double by Santana.
Betts pulled Boston to 2-1 in the first on his ninth homer, but in the top of the second couldn't quite reach a sinking liner by Plawecki that dropped for an RBI single.
Santana hit a two-out homer, his 10th, to make it 7-3, but Boston got three runs in the fourth on Bradley's solo homer and a two-run shot by Benintendi.
Ryan Weber (1-1) gave up seven runs and eight hits in four innings.
Red Sox: LHP Chris Sale (1-6, 4.19) faces New York LHP J.A. Happ (4-3, 5.09) as Boston begins a four-game set Thursday night against the first-place Yankees in the Bronx.