The loss dropped Boston into a tie with the Yankees for the AL East lead. New York visits Fenway Park for a three-game series starting Friday night.
The Indians won for only the fourth time in 15 games. The four-game split prevented Cleveland from falling below .500 for the first time since three games into the season.
Erik Bedard, making his Red Sox debut after being acquired from Seattle, gave up three runs and seven hits in five innings. In his second start since coming off the disabled list, he was on a pitch count and came out after 70 with the score 3-all.
Boston began the day with a one-game lead over the Yankees in the AL East. The Red Sox host New York for a three-game series starting Friday night.
Masterson (9-7) allowed three runs and five hits in six innings. He improved to 3-0 overall against Boston, which traded him to the Indians to get Victor Martinez in 2009.
Masterson also tied a major league record with four strikeouts in the third inning. He is the sixth Indians pitcher, the first since Chuck Finley in 2000, to fan four in an inning. Masterson's wild pitch prolonged the inning.
The Cleveland right-hander gave up two first-inning runs and a solo homer to Josh Reddick in the fourth, leaving after throwing 118 pitches. Three relievers finished up, with Chris Perez working the ninth in a non-save situation.
Santana hit a two-run homer in the sixth for a 5-3 lead. Travis Hafner, who had three hits, led off with a long double against reliever Franklin Morales (0-1) and on the next pitch, Santana, already 2-for-2 with an RBI, hit his 16th home run dead center field.
Hafner's RBI double off Andrew Miller in the seventh and Kosuke Fukudome's RBI double, his third hit, closed the scoring in the ninth.
The Red Sox took a 2-0 lead in the first on an RBI double by Adrian Gonzalez and run-scoring single by David Ortiz. Gonzalez extended his season-high hitting streak to 14 games with his major-league-leading 91st RBI.
The Indians, retired in order by Bedard in the first, tied it in the second. Santana singled and took with on a single by Fukudome, who moved up when Reddick's throw from right field hit Santana.
Matt LaPorta drove in a run with an infield single when Bedard failed to cover first and Austin Kearns' RBI grounder tied it.
Santana's RBI single gave the Indians a 3-2 lead but Reddick tied the game again with his fifth homer of the year.
The game drew 38,477 a post-World War II record at Fenway. … Recently acquired Ubaldo Jimenez makes his Indians debut when he faces 10-game winner Derek Holland, who shut the Indians out June 4, in the opener of Cleveland's three-game series in Texas Friday night. … Jon Lester, 8-1 lifetime against the Yankees and 2-0 this season, faces the Yankees' Bartolo Colon, 0-2 against Boston this year, on Friday night. … Indians LF Michael Brantley missed his second straight game with a sore right wrist. He will take batting practice Friday. Meanwhile, RF Shin-Soo Choo, on the disabled list with a broken left thumb, is hitting and appears to be ahead of the projected return of the last week of August or first week of September. … Indians OF Travis Buck accepted his assignment to Triple-A Columbus. … Cleveland RHP Carlos Carrasco, who started Wednesday night, dropped his appeal and began serving a six-game suspension for throwing high to Kansas City's Billy Butler. … Indians 2B Jason Kipnis saw his home run streak end at four straight games. He is the first player in major league history to homer in four straight within two weeks of the start of his career. Graig Nettles, then of the Twins, was the last player to homer in four straight in the first 10 games of his career, doing it in 1968. Kipnis is the first Indians 2B ever to accomplish the feat. … Miller, in his first Red Sox relief outing, threw 71 pitches in 2 2-3 innings.