Game 4 featured a matchup of two veterans - knuckleballer Tim Wakefield for Boston, and soft-tossing Paul Byrd for Cleveland. Both teams went down quickly in the first four innings. The Red Sox had baserunners in the second and fourth, and two men on in the third, but their bats had gone cold with men on base since their offensive onslaught in the first two games.

The Indians were the first to break through, on Casey Blake's homer to lead off the fifth. But then Franklin Gutierrez singled, moved up when the next batter was hit by a pitch, and went to third on a groundout. Asdrubal Cabrera was next, and he hit a popup foul behind the first base bag. Kevin Youkilis pursued it, as Gutierrez tagged up. As soon as Youkilis got his glove on it, Gutierrez took off, but Youk ended up bobbling it a couple of times and eventually dropping it. That was a break for the Red Sox, because if he had caught the ball, Gutierrez would have been able to score, but once the ball dropped, it was just a harmless foul and the runner had to go back to third. That was the end of the Red Sox' good luck, though, when Cabrera hit a grounder back toward the mound. It probably would have been an inning-ending ground ball if it had gone straight through to the waiting infielders, but Wakefield tipped it on its way by, and it ended up an RBI single, as Gutierrez crossed the plate and the Indians took a 2-0 lead. Travis Hafner struck out, but then Victor Martinez singled, knocking in another run. That was the end of the night for Wakefield, with Manny Delcarmen coming in. Unfortunately, he couldn't stop the bleeding, and Jhonny Peralta launched a three-run homer. But it didn't stop there; Kenny Lofton singled, stole second, and scored on Blake's second RBI hit of the inning. By the time the inning finally ended, the Indians had their second seven-run inning of the series.

Down 7-0, the Red Sox had a huge hole to try to climb out of, but they got started right away. Youkilis homered to lead off the inning. David Ortiz followed with a homer of his own. And after a pitching change, Manny Ramirez got in on the fun, with another home run. It was the first time in history that a team had hit back-to-back-to-back home runs in a League Championship Series game. The Sox had hit four straight in an April game earlier that season, but that wouldn't happen again, as Mike Lowell grounded out. And as suddenly as the fireworks had started, they were done. The Red Sox only had one baserunner the rest of the game, and he was erased on a double play. Once again, the Indians bullpen shut down their offense. Jon Lester pitched three scoreless innings to finish the game, but the seven-run fifth inning proved to be too much. The Indians won the game and took a 3-1 lead in the series.