The AL East Division champion and second-seeded Tampa Bay Rays, who had defeated the Chicago White Sox in the ALDS, were paired with the wild-card and defending world champion Boston Red Sox, who had defeated the Los Angeles Angels of Anaheim, in the ALDS.

Veteran and former World Series champion Cliff Floyd, who had signed with the team in the off-season at age 35, contemplated retirement after the first few days of spring training.

After being a season-long running distraction in the clubhouse,[5] GM Theo Epstein traded superstar Manny Ramirez to the Dodgers in a blockbuster three-way deal.

In the deal, the Red Sox acquired outfielder Jason Bay and minor league infielder Josh Wilson, and the Pittsburgh Pirates got infielder Andy LaRoche and pitching prospect Bryan Morris from the Dodgers and outfielder Brandon Moss and pitcher Craig Hansen from the Red Sox.

The acquisition of Jason Bay proved to be a wake-up call for the defending champs, as they finished with a 34-19 record after the trade and qualified for the postseason as a wild card.

Starter Daisuke Matsuzaka held the Rays hitless until Carl Crawford singled to lead off the seventh inning.

Bay's single in the seventh off Chad Bradford scored Pedroia, who walked off J. P. Howell with one out earlier that inning.

In the bottom of the 11th, Mike Timlin walked three to load the bases before a sacrifice fly by Upton allowed Fernando Perez to score the winning run.

The 3–4–5 hitters went 0–9 against him and the Red Sox's only run came in the seventh on Jacoby Ellsbury's sacrifice fly off J. P. Howell that scored Jason Varitek, who walked off Garza to lead off the inning.

In the eighth, New England native Rocco Baldelli hit a three-run homer of his own, also over the Green Monster, off Byrd to seal the win.

Kevin Cash's leadoff home run in the third off Rays starter Andy Sonnanstine put the Red Sox on the board.

In the bottom of the seventh, with two outs and runners on first and third, Dustin Pedroia hit an RBI single off Grant Balfour to finally get the Red Sox on the board.

In the ninth inning, after J. P. Howell retired the first two Boston batters, Kevin Youkilis hit a ground ball to third base.

After an intentional walk to Jason Bay, Drew hit a single over the head of right fielder Gabe Gross to win the game.

Josh Beckett pitched five innings and allowed two solo home runs, to B. J. Upton in the first and Jason Bartlett in the fifth, to record the win.

Umpire Derryl Cousins was struck by a foul ball from Varitek in the second inning, leaving the game with a bruised collarbone after the third.

The network picked up the game just prior to the last out in the bottom of the first, with announcer Chip Caray apologizing to viewers for "technical difficulties".

In the eighth, David Price, who made his major league debut a little over a month before came on to pitch to J. D. Drew with the bases loaded and struck him out on a checked swing.

In the ninth, Price recorded his first Major League save by getting Jed Lowrie to ground into a force play to Akinori Iwamura.

With the win, the Rays became the second team to go to the World Series after posting the worst record the year before, joining the 1991 Atlanta Braves, who went on to lose to the Minnesota Twins.

From 2010–2013, the Rays won at least 90 games each season, a remarkable feat for a team with one of the lowest payrolls in baseball, particularly in a division with the Yankees and Red Sox.