The Red Six tuned up for the playoffs by opening a two-game lead over Oakland for the best record in the American League.
Shane Victorino snapped a 4-4 tie with a three-run home run in the fourth and Middlebrooks hit a three-run blast of his own one inning later.
Middlebrooks highlighted a five-run eighth with a grand slam, giving him 17 home runs for the season.
Although Jake Peavy did not have an excellent outing, the powerful Boston offense gave him an easy win.
Peavy (12-5) gave up five runs on eight hits over six innings. He walked four and struck out five.
The first seven Boston runs were scored against Jhoulys Chacin (14-10).
It was the final home game for Colorado first baseman Todd Helton, who holds the franchise record in most offensive categories. He has announced this will be his final season after spending all 17 of his major league years with Colorado.