The Red Sox have home-field advantage throughout the playoffs by winning the season series against Cleveland, five games to two, although both teams finished with 96–66 records.

The Red Sox tied the game in the bottom of the inning off of CC Sabathia on three straight one-out singles by Kevin Youkilis, David Ortiz, and Manny Ramirez.

In the top of the fourth, Jhonny Peralta hit a three-run blast into the camera well in center field off Schilling, giving the Indians a 4–3 lead.

In the top of the sixth, Peralta drew a leadoff walk off of reliever Manny Delcarmen, moved to third on a single and scored on Franklin Gutierrez's groundout to tie the game 6–6.

[9] One of the highlights was the go-ahead RBI base hit by former Red Sox right fielder Trot Nixon off Boston's lefty specialist Javier López after a one-out and single off of Eric Gagne.

After retiring Víctor Martínez, López gave up a single to Ryan Garko and was lifted for Jon Lester, the only pitcher left in the Boston bullpen.

Lester did not fare much better; Peralta greeted him with a run-scoring double, which was followed one out later by Franklin Gutiérrez's three-run homer, capping the scoring.

Coming off a lopsided 13–6 loss in 11 innings, Boston sent Daisuke Matsuzaka to the mound to face off with Jake Westbrook for Game 3 at Jacobs Field.

Casey Blake led off the inning with a homer off Wakefield, Franklin Gutiérrez singled, Kelly Shoppach was hit by a pitch, and Grady Sizemore reached on a fielder's choice.

After Kevin Youkilis bobbled and dropped a foul ball, Asdrúbal Cabrera reached on an infield single as Gutiérrez scored.

At that point, Boston skipper Terry Francona yanked Wakefield for reliever Manny Delcarmen, who gave up an opposite-field home run to Jhonny Peralta on a 2–1 pitch.

The Red Sox answered immediately when Youkilis and David Ortiz hit back-to-back homers, chasing Indians starter Paul Byrd in favor of rookie reliever Jensen Lewis.

However, that would be all the offense the Red Sox could muster as the Indians took a three games to one lead in the series behind Byrd, Lewis, and fellow reliever Rafael Betancourt.

[citation needed] Cleveland also played the All American Rejects hit song "It Ends Tonight" before the game, predicting that the Indians would win and eliminate the Red Sox that evening.

Facing elimination in Game 5, the Sox struck first with a home run from Kevin Youkilis in the top of the first inning off of CC Sabathia.

Meanwhile, Josh Beckett pitched eight dominant innings for the Red Sox, and collected 11 strikeouts, tying a career post-season high.

Jonathan Papelbon pitched a scoreless ninth despite allowing a double and walk as the Red Sox's 7–1 win ensured a return trip to Boston for Game 6.

After Curt Schilling retired the Indians in the top of the first, the Red Sox loaded the bases on infield hits by Dustin Pedroia and Kevin Youkilis plus a full-count walk to David Ortiz.

Ryan Garko started the top of the seventh with a triple and scored on a Jhonny Peralta sacrifice fly, but that would be all the offense Cleveland could muster against Schilling on the night.

Boston's top two relief pitchers took over after Matsuzaka's exit following the fifth inning; Hideki Okajima and Jonathan Papelbon were able to hold Indians hitters scoreless over the final four frames, giving up just four hits combined, all singles.

Rookies Jacoby Ellsbury and Dustin Pedroia were the center of the offense in the seventh with Ellsbury reaching second on a Blake error then Dustin Pedroia hit a two-run home run off of Rafael Betancourt into the Green Monster seats, giving the Red Sox some insurance runs, before they put up a six-spot in the bottom of the eighth against the collapsing Cleveland bullpen.

After a ground-rule double, intentional walk, and strikeout, a three-RBI double by Pedroia knocked Betancourt out of the game, then a two-run Kevin Youkilis home run off of Jensen Lewis made it 11–2 Red Sox, which cemented their victory and led to their second American League championship and World Series appearance in four years.