The two teams met up for Game 6 with the Indians leading the series 3-2 and feeling confident. After failing to finish the Red Sox off at home in Game 5, first baseman Ryan Garko quipped, "Champagne tastes just as sweet on the road." But the game was in Boston, and the Red Sox had postseason ace Curt Schilling on the mound. He was opposed by 23-year-old Fausto Carmona, in a rematch of Game 2, in which neither pitcher had fared well.

Curt pitched an efficient 1-2-3 inning in the first, and the Red Sox came to the plate. Dustin Pedroia, who had been quiet early in the series until finally getting two hits in Game 5, picked up where he left off with an infield single up the middle. Kevin Youkilis followed with another well-placed infield smash and reached safely. David Ortiz took a walk, loading the bases with no outs. Manny Ramirez had a very long at-bat, fouling off pitch after pitch, but he ended up striking out. Mike Lowell hit a fly to right field, but it was too shallow to score a run. All of a sudden it looked like the inning would go to waste. Youkilis, Ortiz, Ramirez, and Lowell had been doing most of the damage in the series, and once Cleveland pitchers got past them, it had been easy to retire the bottom of the lineup. Now, with the bases still loaded and two outs, any scoring in the inning would be up to J.D. Drew. He had signed a large contract before the season, but so far he hadn't really lived up to it. He only had 11 home runs in the regular season, and hadn't knocked in a run during the whole ALCS. But he worked a 3-1 count, and then launched a huge shot to center field. It landed in the area of the center field cameras, a grand slam that gave the Sox a 4-0 lead and got Fenway Park rocking.

The Indians got one run back the next inning, when Victor Martinez launched a homer past Pesky's Pole. Cleveland got two runners on to open the third, too, but Curt was able to retire the top three batters in the order to end the threat. Carmona had control issues in the third, as he walked Ramirez and Lowell to open the inning. Drew got a standing ovation as he came to the plate, and he continued his hot night, lining a single into center that drove home his fifth run of the game. That brought in Rafael Perez from the bullpen, and it opened the floodgates. Coco Crisp had struggled badly in the postseason, and he had been replaced in the starting lineup for Game 6 with rookie Jacoby Ellsbury. Ellsbury singled, driving in another run, and Julio Lugo doubled to bring two more home. Pedroia walked, and then Youkilis banged one off the Monster. Lugo scored easily, and Pedroia reached third as Youk made the turn at first. Kenny Lofton fielded the ball and threw it to second base, where they had Youk tied up halfway between first and second. But the throw from second baseman Asdrubal Cabrera bounced off Youk's helmet, and he was able to dive safely into first as Pedroia crossed the plate with the Sox' tenth run. The next play was a bouncer from Big Papi to Garko at first. He stepped on the bag to retire Papi, but then his throw to second sailed into center field for an error. After Manny walked, Lowell flied out to finally end the inning with the Red Sox up 10-1.

Staked to a big lead, Schilling rolled through the Cleveland lineup. He allowed his share of baserunners, but prevented them from doing any damage. In the seventh, Garko tripled just over Ellsbury's head in left center, and a sacrifice fly got the Indians just their second run of the game. The Sox got the run back - and more - in the eighth. With Youkilis on third and Papi on second after a walk and a double, Manny drove home one run with a sac fly, and Lowell's single plated another. Drew followed with his third hit of the game.

The ten-run lead meant Terry Francona could bring in Eric Gagne for the ninth. He got a fly ball and two groundouts, for a rare 1-2-3 inning. The Red Sox had come back to even the series, making a winner-take-all Game 7 necessary the next night.