In the opener, Jamie Moyer allowed only two soft singles in seven shutout innings and Greg Dobbs hit a three-run homer off Pedro Martinez, leading the Phillies to a 6-2 victory.
That put the pressure on Santana (13-7), acquired from Minnesota last offseason and signed to a $137.5 million, six-year contract. A win in the nightcap would leave New York atop the division with 19 games to play. A loss would create a first-place tie and stir painful memories of last September's epic collapse.
With plenty of help from Delgado, Santana delivered - on his own bobblehead night. And as Serena Williams played Jelena Jankovic next door for the U.S. Open tennis title, the Mets held serve.
Cole Hamels hung an 0-2 breaking ball to Delgado leading off the third and he jumped on it, hitting a drive estimated at 400 feet off the bottom of the right-field scoreboard.
Hamels (12-9) tossed his head back in frustration as soon as Delgado connected and soon received a mound visit from bench coach Jimy Williams, running the team after manager Charlie Manuel was ejected in the first inning for arguing a catcher's interference call.
Delgado's solo shot in the fifth soared past the second deck of seats in right and beyond New York's bullpen, toward the Shea Stadium parking lot.
With the crowd chanting "MVP! MVP!" Delgado came out for a curtain call. It was his 48th multihomer game and sixth this season, one short of Dave Kingman's club record set in 1976.
After a slow start that had fans and talk-show hosts calling for his release, the 36-year-old Delgado leads the majors with 22 homers since June 27. His 65 RBIs during that stretch are tops in the NL.
Delgado, who has 464 career homers, also hit a two-run single in the first. He was cheered after striking out in the seventh.
Ryan Howard's solo drive in the third cut Philadelphia's deficit to 3-2 and made him the first Phillies player with three straight 40-homer seasons. Howard also had an RBI single in the first.
Santana was pulled after Jayson Werth's one-out double in the eighth on his 116th pitch. The two-time AL Cy Young Award winner tipped his cap to the crowd of 54,980 and got a warm greeting in the dugout.
Pedro Feliciano retired Howard, and Brian Stokes got Mets nemesis Pat Burrell to ground out on his only pitch. Luis Ayala allowed a run in the ninth but struck out Jimmy Rollins with a runner on to end it.
Between games, however, the Mets got bad news about their suspect bullpen: Injured closer Billy Wagner felt pain while testing his ailing elbow, throwing to a New York hitter in a virtually empty stadium. Wagner will be re-examined by a doctor Monday and his return appears uncertain.
The Phillies skipped Kyle Kendrick's turn in the rotation so their own ace, Hamels, would get a start on four days' rest in this crucial series - though the 24-year-old lefty didn't exactly demand the ball.
Hamels never looked comfortable, allowing five runs - four earned - and nine hits in five innings. Carlos Beltran had an RBI single in a three-run first, when David Wright reached on catcher's interference against Chris Coste.
Damion Easley hit a leadoff triple in the eighth and scored on Brian Schneider's sacrifice fly.
In the opener, a makeup of Saturday's rainout, the 45-year-old Moyer (13-7) allowed only a surprise bunt single by Robinson Cancel and an infield hit by Easley. New York was scoreless for the first 16 innings of the series before breaking through for two runs in the eighth against Scott Eyre.
Manuel wanted to make sure his team stayed focused for the nightcap. After the first game, he posted a sign in the clubhouse that read: "No football on any TV after 7:15." The Phillies swept a three-game series at Shea Stadium last September, beginning their charge past the collapsing Mets to win the division title. But Philadelphia couldn't complete the trick this time.
Asked between games if this series was starting to rekindle bad memories of last year, Wright had a one-word answer: "No."
Moyer's 243rd win tied him with Hall of Famer Juan Marichal for 50th on the career list.
Martinez (5-4) lasted only four innings, giving up six runs and seven hits.
Notes: Philadelphia went 7-11 against the Mets this season after winning the final eight matchups last year. ... Wagner faced teammate Gustavo Molina between games and walked off the mound after hitting him on the left foot with his 13th pitch. The lefty consulted with a trainer and the Mets' coaching staff.