Bautista, who leads the majors with 31 homers, connected on a 1-0 pitch from Chris Perez (3-2) after the Indians tied it on Travis Buck's two-out double in the ninth. The slugger has four multihomer games this season and 15 in his career.
Bautista's towering to drive to left cleared the 19-foot wall. He said he wasn't trying to hit a home run, but he wasn't thinking about just reaching base either.
''I'm not necessarily trying to walk or hit a single,'' said Bautista, who hit a drive over the same wall in the third inning. ''I was looking for a fastball middle or middle-in. He tried go away, but he missed inside. I was ready for it.''
''That's why he's our best player,'' Toronto manager John Farrell said. ''He comes through in moments like that, not just when you're down three or four or up three or four.''
Bautista tries to approach every at-bat the same.
''I don't think it makes that much of a difference,'' he said. ''I feel comfortable right now. I'm not saying I feel like I'm going to get a hit every time, but I feel like I can hit the ball hard if the pitch is thrown where I'm looking for it.''
Indians manager Manny Acta pointed to another elite slugger while describing Bautista's impressive roll.
''Right now he is reminding me of the way Barry Bonds was when he was in his prime,'' Acta said. ''When you make a mistake, he will not foul it off. He just hits it out. He will not even hit it off the wall. He just hits it out.''
It was Toronto's second straight win in the series after a stunning loss on Thursday during which the Indians rallied for a 5-4 win on Travis Hafner's game-ending grand slam in the ninth.
Cleveland nearly pulled off another memorable comeback Saturday. Hafner started the ninth with a single and Carlos Santana followed with a grounder that glanced off reliever Jon Rauch's glove and rolled to first baseman Adam Lind. Rauch (3-3) raced to the bag and took the throw, which was barely in time to beat Santana's headfirst slide.
Pinch-runner Austin Kearns moved to second on the grounder and advanced again when Grady Sizemore tapped back to the mound. Buck then doubled off the wall in left-center on the 11th pitch of the at-bat. Matt LaPorta grounded out to end the inning.
Shawn Camp pitched a perfect 10th for his first save.
Toronto starter Brandon Morrow allowed three runs and three hits over eight innings in his longest outing of the season. He struck out eight and walked two.
Bautista lined a 1-0 pitch from Josh Tomlin into the bleachers in left field with two outs in the third, giving Toronto a 2-1 lead. Bautista also became the first major leaguer to hit 30 homers before the All-Star break since Alex Rodriguez in 2007, and set a club record for home runs before the break, snapping a tie with George Bell, who hit 29 in 1987.
''He's playing a game almost like he's playing it in his backyard,'' Farrell said. ''He's free, he's loose and his talent is extraordinary.''
An error by Buck, the first of his career, helped the Blue Jays go in front 4-3 in the fifth. His errant throw after Lind's single to right allowed Eric Thames to score. Buck had played 192 games without committing an error.
Sizemore hit a two-run homer in the fourth to tie it at 3.
NOTES: Toronto is 25-25 on the road. ... Ten of the Blue Jays' last 13 games have been decided by two runs or less. Toronto is 3-7 in those games. ... Bautista became the quickest player in Toronto history to reach 100 home runs. He accomplished the feat in 377 games. ... Jose Molina doubled twice off Tomlin and is 4 for 5 against the right-hander in his career. ... Acta said OF Shin-Soo Choo has had the cast removed from his broken right thumb. The Indians expect Choo, who was injured on June 24, to return this season. ... Indians 3B Lonnie Chisenhall (nasal fracture) played catch Saturday. He was hit in the face with a pitch Thursday.