Aaron Rowand gave the Giants a one-run lead with a solo shot leading off the top of the inning, but the Phillies rallied against Brian Wilson (0-1).
Chase Utley singled with one out. After Ryan Howard was ejected after striking out, Burrell hit a 3-2 pitch into the left-field seats, sending the crowd into a frenzy on a chilly night.
It was Burrell's third career game-ending homer, and first since 2002. He paused to admire his shot briefly, before circling the bases and getting mobbed by teammates. Burrell then popped out of the dugout for a curtain call.
"It's been a while," Burrell said. "It's a nice feeling, especially after we had the lead."
Wilson, who was 9-for-10 in save chances, fell behind in the count 3-0 on three straight fastballs, one reaching 98 mph. Burrell swung through a fourth and fouled off the fifth one, before ripping the last pitch over the wall.
"To be honest, I was just hoping to see the ball," Burrell said. "He was throwing pretty hard."
Said Wilson: "I left it right over the middle."
Utley and Pedro Feliz each hit two-run homers for Philadelphia, which has won nine of 12.
The Phillies are 13-9 since shortstop Jimmy Rollins injured his ankle on April 8. The 2007 NL MVP won't come off the disabled list when he's eligible Monday, but is hoping to return for Thursday's game in Arizona.
Playing his first game against his former team, Rowand got a standing ovation his first time up. Fans booed as he rounded the bases after connecting off J.C. Romero (2-0).
Romero, the Phillies' left-handed relief ace, hadn't allowed an earned run in 28 1-3 innings, dating to last season. He pitched 12 2-3 scoreless innings this year before Rowand took him deep. It was the first homer Romero allowed in 60 appearances, spanning 45 2-3 innings.
But Burrell's homer erased Romero's blemish. He has nine homers and 28 RBIs along with a .330 average. The days when Burrell was getting booed regularly by fans are long over.
"He's swinging the bat real good," manager Charlie Manuel said. "He's been real clutch for us. He works hard. He studies the game. He studies the starting pitcher. Hopefully, he keeps it going."
Trailing 4-1 in the seventh, the Giants chased Phillies starter Kyle Kendrick with consecutive singles and tied it off Ryan Madson. Ray Durham hit a two-run single and Bengie Molina's RBI groundout tied it at 4. Madson struck out Rowand to leave two runners on.
In the first, Utley ripped one into the right-field seats for his major league-leading 12th homer, giving the Phillies a 2-0 lead. It would've been a solo shot if second baseman Durham hadn't overrun Jayson Werth's popup down the right-field line and let it fall for a single.
Feliz connected against his former team in the fourth to make it 4-1. Feliz signed a two-year contract with the Phillies in January, leaving the Giants on slightly bad terms.
Rowand left Philadelphia after two seasons for a $60 million, five-year contract. Revered in Philly for busting his face after running into the fence while making an outstanding catch in 2006, Rowand got a warm welcome when he came to the plate in the second inning. Rowand tipped his helmet to the crowd then struck out on three pitches.
"It was an emotional moment," Rowand said. "I can't thank the fans enough."
Rowand doubled and scored the Giants' first run on Jose Castillo's single in the fourth.
Kendrick allowed three runs and eight hits in six-plus innings, striking out a career-best six.
Giants starter Pat Misch allowed four runs and five hits in four innings in his fifth career start and first this season.
Notes: Hall of Fame 3B Mike Schmidt was in Philadelphia to promote the launching of his own wine label. Other members of the 500 home run club, Eddie Murray and Ernie Banks, are doing the same. All proceeds will go to charity. Schmidt was walking to an elevator when he spotted a fan wearing his No. 20 retro jersey. "Hey, nice jersey," he yelled. ... Giants 1B John Bowker snapped an 0-for-14 slump with a career-best four hits. ... San Francisco had a season-high 16 hits. ... The left-handed hitting Utley leads the majors with six homers off left-handers.
