Shane Victorino hit a bases-loaded triple, and Ryan Howard and Jayson Werth hit the Phillies' first back-to-back homers of the season to end the Yankees' nine-game home winning streak.
Philadelphia roughed up A.J. Burnett (6-5) for only its ninth win in 26 games, a stretch that has dropped them into third place in the NL East.
On Thursday, the Phillies will face Andy Pettitte in the finale of the three-game set. Pettitte won the clincher in last year's World Series between the two teams.
Alex Rodriguez returned to the Yankees' lineup after missing four games because of tendinitis in his right hip and went 1 for 3 with a walk and an RBI double as the designated hitter. He twice hit soft flyballs in front of the warning track on pitches barely reaching 80 mph.
Moyer (7-6) repeatedly lulled the Yankees into lazy outs with an array of tosses that were slow and slower, some in the mid 60s, and allowed just three hits. His only mistakes went a long way, though. Robinson Cano and Jorge Posada homered for New York's first two hits.
Moyer earned his 265th lifetime victory. He struck out five, walked one and left with a 6-2 lead.
The Yankees scored once off Brad Lidge in the ninth on Rodriguez's double before Posada struck out with two on to end the game.
Phillies manager Charlie Manuel flopped Moyer and Kyle Kendrick in the rotation so he could pitch a lefty after right-hander Roy Halladay, who was hit hard in an 8-3 loss Tuesday. Kendrick pitched in relief Friday, when Moyer allowed nine runs and got just three outs at Boston.
Moyer's been around too long to let that start at Fenway Park affect him. He picked at the corners all night, four times getting the Yankees to look at strike three.
Moyer beat the Yankees at 47 years, 155 days. The previous oldest pitcher to beat them was Phil Niekro at 47 year, 122 days, according to the Elias Sports Bureau.
Greg Dobbs, in the lineup because he was 4 for 6 for his career against Burnett, hit an RBI single in the second after Raul Ibanez walked and stole second.
Burnett then walked Brian Schneider and Wilson Valdez, the No. 9 hitter, singled before Victorino hit a drive to center that cleared the bases. The many red-clad Phillies' fans in the crowd of 47,414 let out a loud cheer.
Cano homered in the bottom half about halfway up the bleachers in right-center for his 14th of the season.
But Howard led off the third with a shot to the left of Monument Park in center field and Werth followed with one to right for a 6-1 lead.
Yankees manager Joe Girardi removed Burnett with one out in the fourth after he failed to cover first on a sharp grounder down the first base line that Mark Teixeira made a tough play to field but had no one to toss to, giving Chase Utley an infield single.
NOTES: Belmont Stakes-winning trainer Bill Mott threw out the ceremonial first pitch. In addition to training Belmont winner Drosselmeyer, Mott also trains horses for Kinsman Farm in Ocala, Fla., owned by Yankees owner George Steinbrenner. ... Phillies C Carlos Ruiz, in an 0-for-22 slide, was out with a sore ankle. ... Paul Simon and Art Garfunkel were at the game, sitting next to each other.
