Rodriguez flopped in crucial spots all night. He grounded into two double plays -- one with the bases loaded -- and whiffed for the final out.
"Tonight, you can put it on me," Rodriguez said. "It was a lousy night. We pretty much screwed it up every way you can screw it up. There's absolutely no excuse."
Jason Bay drove in two runs, David Ortiz had a strong game at the plate and Boston got an outstanding effort from its bullpen to close out the opener of a key three-game series. The Red Sox moved within 3½ games of first-place Tampa Bay in the AL East.
Johnny Damon hit two solo homers for the Yankees, but Rodriguez's failures thwarted one potential rally after another.
"He's the best player in the league. Unfortunately, he had a bad night," Damon said.
This is Boston's final regular-season visit to Yankee Stadium, the site of so many memorable moments throughout the teams' long rivalry. Next year, New York moves into a lavish new ballpark being built across the street, and this isn't the way A-Rod and the Yankees wanted to say goodbye.
The three-time MVP finished 0-for-5 and was booed loudly as New York fell six games behind Boston, which leads the wild-card race by a slim margin over Minnesota. Rodriguez also committed an error at third base.
With a couple more wins this week, the Red Sox can leave the Yankees with a huge hill to climb and little time left to do it. New York hasn't missed a postseason since 1993.
Wakefield (8-8) allowed three runs and eight hits in five innings after entering 0-5 with an 8.91 ERA in his previous six starts against the Yankees. The 42-year-old knuckleballer hadn't pitched since Aug. 6 because of tightness in his right shoulder.
"He didn't have his best knuckleball tonight, but it was plenty for his first time back," Boston manager Terry Francona said.
Five Red Sox relievers combined for four scoreless innings, and Jonathan Papelbon got four outs for his 34th save in 38 chances.
"Phenomenal job," Wakefield said.
Usually reliable in big games, Pettitte (13-10) was touched for six runs and 10 hits in 4 2/3 innings.
"It was just one of those nights," he said. "I deserved to get booed."
Playing his first game in the rivalry, Bay had an RBI single in the third and a sacrifice fly in the sixth.
Even without Manny Ramirez batting behind him, Ortiz tormented the Yankees as usual with two doubles and two walks.
"I like playing here," he said. "I was taking my walks and doing my thing."
Coco Crisp got three hits and dashed home from second on Jeff Bailey's two-out infield single off the third-base bag in the fifth. First baseman Jason Giambi held onto Rodriguez's throw as Crisp scored. Bailey was credited with two RBI, chasing Pettitte and capping a three-run rally -- all with two outs.
Rodriguez flied out with two on in the bottom half. With the Yankees trailing 7-3 in the seventh, he came up with the bases loaded and grounded into an inning-ending double play against rookie Justin Masterson.
"Poise is not a problem for him," Francona said. "He gives us options. We feel comfortable using him late in the game and he deserves it."
That left A-Rod 1-for-10 this season with the bases loaded -- 0-for-7 when there were less than two outs.
"I want him in that situation," Yankees manager Joe Girardi said. "I've seen him change a game with one swing."
A-Rod, who struck out twice, also bounced into a double play that ended the third. He has grounded into nine double plays in his last 19 games.
"No one is more frustrated than me," said Rodriguez, adding that he'll show up early Wednesday for extra hitting work with batting coach Kevin Long.
- RHP Joba Chamberlain, on the DL with rotator cuff tendinitis, will throw another bullpen session Thursday. The Yankees will then determine what his next step is.
- Playing in shallow right field, Boston 2B Dustin Pedroia booted Jason Giambi's leadoff grounder in the eighth -- ending his 61-game errorless streak.
- The Yankees had won 15 of 20 at home.
- Damon, a former Red Sox star, hit his 23rd career leadoff homer. It was his 11th career multihomer game.
- The sellout crowd of 55,058 included Tiger Woods, who sat behind home plate.
- Boston put RF J.D. Drew (back) on the 15-day DL.