He took two of them off Toronto star pitcher RA Dickey, winner of last year's NL Cy Young Award with the New York Mets, who took flak from some of the riled home support as he allowed 10 hits and gave up eight runs - seven earned - in 4 2/3 innings.
Middlebrooks also scored a home run off Dave Bush who conceded further homers to Daniel Nava, Jacoby Ellsbury and Mike Napoli as the Red Sox had a rampant game.
The Tampa Bay Rays were humiliated by the same score in their Tropicana Field clash with the Cleveland Indians, for whom Mark Reynolds and Lonnie Chisenhall blasted three-run homers.
Oddly it was the AL's Cy Young Award winner from last year, David Price, who took the brunt of the punishment, being flogged for 10 hits and eight runs - all earned - in five innings.
Another shutout in the American League came in Detroit where the Tigers slumped to a 7-0 loss against the New York Yankees, while home runs from Lance Berkman, David Murphy and Ian Kinsler helped the Texas Rangers to a 7-3 win against the Los Angeles Angels.
The Minnesota Twins edged the Baltimore Orioles 4-3, and the Chicago White Sox also won 4-3, in their case after a 10th-inning homer from Dayan Viciedo against the Seattle Mariners.
Brett Anderson trashed the Houston batting line-up with 10 strikeouts in the Oakland Athletics' 9-3 win over the Astros.
Matt Cain went the other way, giving up nine runs as the San Francisco Giants were pummelled 14-3 by the St Louis Cardinals in perhaps the standout - for the wrong reasons - performance in the National League.
Eric Hinske led the Arizona Diamondbacks to an 8-7 win against the Milwaukee Brewers by going deep for two runs in the 11th inning, while the Atlanta Braves beat the Chicago Cubs 5-1 and the Cincinnati Reds enjoyed a 6-3 home victory over the Washington Nationals.
Dexter Fowler's two-run homer in the first inning was followed by a three-run homer by Wilin Rosario in the seventh as the Colorado Rockies beat the San Diego Padres 9-1, but a two-run homer in the first inning from Andrew McCutchen brought no reward for the Pittsburgh Pirates who went on to lose 6-2 against the Los Angeles Dodgers.
The New York Mets beat the Miami Marlins 4-3, with Marlon Byrd making the difference in the bottom of the ninth with a two-run walkoff single.
Billy Butler hit a grand slam in the fifth inning of the inter-league tussle between Kansas City and Philadelphia, and finished with seven RBIs in helping the Royals record a 9-8 win against the Phillies.