Middlebrooks has five home runs and 10 extra base hits in 13 career games at Toronto's Rogers Centre. He had a three-homer game against the Blue Jays on April 7, 2013.
Boston's Clay Buchholz survived a shaky first inning to win for the first time in five starts this season. Buchholz (1-2) allowed three runs and six hits in seven innings, bouncing back from a shaky start against Baltimore last Monday in which he allowed six runs in 2 1-3 innings.
Buchholz, who walked three and struck out three, is 8-2 with a 1.72 ERA in 11 career starts at Toronto.
Junichi Tazawa replaced Buchholz to begin the eighth but gave up a leadoff homer to Francisco. Back-to-back singles and a fielder's choice put runners at the corners for pinch hitter Edwin Encarnacion, who hit an RBI single. Chris Capuano replaced Tazawa and struck out pinch hitter Jonathan Diaz before walking Jose Reyes to load the bases. Koji Uehara came on and ended the inning by getting Melky Cabrera to fly out.
Uehara gave up Bautista's leadoff homer in the ninth but got Encarnacion to fly out with men at first and second for his fifth save in as many chances.
Blue Jays right-hander Brandon Morrow (1-2) issued a career-worst eight walks in 2 2-3 innings, allowing four runs without giving up a hit.
Morrow, who struck out one, became the first pitcher to allow four or more runs without a hit since Dontrelle Willis gave up five runs and no hits while pitching for Detroit on June 4, 2009.
The Blue Jays jumped on Buchholz with three runs in the first. Bautista hit an RBI single and a second run scored on a wild pitch before Dioner Navarro drove in Bautista with a single off the wall.
Morrow walked two batters in each of the first and second innings, but got double play grounders to escape each time.
Morrow's luck ran out in the third, when he walked four straight after retiring the first two batters of the inning. Chad Jenkins, who was recalled from Triple-A Buffalo following Friday's game, came on for Morrow but Pierzynksi hammered his second pitch over the wall for a grand slam. For Pierzynski, it was his first grand slam since May 2, 2009.
Five pitches later, Middlebrooks connected, the second time this season the Red Sox have hit back-to-back homers.
NOTES: The Blue Jays record for walks in a game is nine, set four times. Jim Clancy, Chris Carpenter, Jesse Jefferson and Pat Hentgen all walked nine batters in one game. ... Blue Jays pitching coach Pete Walker was ejected for arguing during a coaching visit to the mound in the third. ... Diaz, who played five games for the Red Sox last season, got his 2013 World Series ring from manager John Farrell, assistant general manager Mike Hazen and third base coach Brian Butterfield before the game. ... Boston LH Jon Lester (2-3) faces Toronto's R.A. Dickey (1-3) in Sunday's series finale.