It was the longest game between the two teams since the Red Sox won Game 6 of the 1975 World Series on Carlton Fisk's 12th-inning homer.
Craig Breslow (1-0) pitched one inning of scoreless relief for the win.
Logan Ondrusek (0-2) took the loss. He pitched a scoreless 11th but gave up singles to David Ortiz and Mike Napoli before Sizemore lined one off the left-field Wall. The outfielders did not even bother retrieving it as Ortiz scored easily.
Dustin Pedroia had three hits, including two doubles, and Sizemore also had three hits for the Red Sox, who won for the third time in four games. Napoli drove in a pair of runs as the Red Sox opened a 3-1 lead only to see Junichi Tazawa give it up in the eighth.
Cincinnati beat the Red Sox in the '75 Series in seven games despite Fisk's 12th-inning homer in Game 6. The teams also met for interleague series in 2005 and `08.
Red Sox starter Felix Doubront allowed one run on five hits, but he walked two batters in the sixth before leaving with one out and a 3-1 lead. Burke Badenhop threw one pitch to Skip Schumaker to get an inning-ending play.
It was still 3-1 in the eighth when Joey Votto drew a one-out walk and Brandon Phillips doubled to put runners on second and third. Todd Frazier singled in one run, and Ryan Ludwick tied it 3-all with a sacrifice fly.