Wright finished 4-for-4 with two RBIs and a walk.
Pinch-hitter Greg Dobbs hit a three-run homer off reliever Aaron Heilman to cut the Phillies' deficit to 5-4 in the eighth, but the Mets bullpen held on. Billy Wagner pitched a perfect ninth for his third save.
Facing the defending NL East champions for the first time since joining New York, Santana showed why the Mets made him the highest-paid pitcher in major league history.
The two-time AL Cy Young award winner kept a potent lineup off balance with his trademark changeup while mixing in quite a few sliders.
Hamels (2-2) gave up five runs - four earned - and eight hits in seven-plus innings.
The Mets beat the Phillies for the third straight time after losing nine in a row over two seasons. Jimmy Rollins, the 2007 NL MVP, has been out of the lineup for each of New York's wins. He hasn't started the last nine games since spraining his left ankle in a win over the Mets on April 8.
When New York acquired Santana from Minnesota in late January, the move prompted Carlos Beltran to declare the Mets were the team to beat in the division. That was a right-back-at-you message to Rollins, who made the bold prediction last year and followed through by leading the Phillies to their first NL East title in 14 years.
Santana certainly delivered in his first start against the Phillies in six years. He left after allowing consecutive singles to start the bottom of the eighth. Heilman entered to face Dobbs, who drove a pitch into the right-field seats.
Carlos Delgado's sacrifice fly off Brad Lidge gave the Mets a two-run cushion in the ninth. First baseman Ryan Howard's error - the 17th committed by the Phillies this season - led to the unearned run.
After Chase Utley's homer to center cut it to 2-1 in the seventh, the Mets added insurance runs.
Ryan Church led off the eighth with a single and Wright followed with a double. J.C. Romero replaced Hamels after an intentional walk to Beltran loaded the bases, and Delgado drove in a run with an groundout. Angel Pagan's RBI double and Brian Schneider's run-scoring single made it 5-1.
Wright ripped an RBI double to give the Mets a 1-0 lead in the first. His triple scored Jose Reyes to put the Mets ahead 2-0 in the third.
Reyes was shaken up when he hit his head on second baseman Utley's knee on a headfirst slide while stealing second. After a 5-minute delay, Reyes stayed in. An impatient crowd booed while Hamels tossed warmup pitches as a trainer attended to Reyes. Wright lined the next pitch to center, past a sliding Jayson Werth.
Rollins wasn't available to pinch-hit because he left the team to attend a funeral for an uncle. The switch-hitting shortstop is supposed to return to Philadelphia on Saturday, though it's uncertain whether he'll be in the lineup.
