The Phillies, who won the opener 3-1, reduced their magic number for clinching a fifth straight NL East title to two.
Jose Lopez spoiled Lee's shutout bid when he hit a tying home run on an 0-2 pitch in the ninth.
Lee struck out 12 and allowed five hits in nine innings, failing to earn his 17th win.
John Mayberry Jr. gave the Phillies a 1-0 lead when he lined a homer just inside the left-field foul pole in the sixth. It seemed that would be enough for Lee, who now has fallen one out shy of a shutout in two of his last four starts.
Michael Schwimer (1-0) tossed a scoreless 10th for his first career win.
Michael Martinez walked to lead off the 10th against Burke Badenhop (2-2). Howard then lined a 3-1 pitch deep to left-center and the speedy Martinez scored easily.
In the opener, Kyle Kendrick threw five sharp innings for the Phillies.
Kendrick (8-6) didn't allow a hit until Logan Morrison homered to lead off the fifth. He gave up one run and one hit, striking out six.
Lee, the 2008 AL Cy Young Award winner, lowered his ERA to 2.38. His latest gem came a day after Roy Halladay beat Houston 1-0. Halladay, the reigning NL Cy Young Award winner, Lee and the Dodgers' Clayton Kershaw are the top three candidates for the award this season.
Lee has twice been the NL Pitcher of the Month this year. He was 5-0 with a 0.21 ERA in June and 5-0 with a 0.45 ERA in August.
The major league-leading Phillies (97-51) moved within five wins of setting a single-season franchise record.
Alex Sanabia allowed one run and six hits in six innings in Game 2. Anibal Sanchez (8-8) pitched six strong innings, but was the hard-luck loser in the opener. He gave up two runs and four hits, striking out seven.
Kendrick's reward for a strong start could be meaningful work as a reliever in the postseason. With four aces and Vance Worley ahead of him on the depth chart, Kendrick will be back in the bullpen in October.
"Whatever they need me to do," Kendrick said. "Obviously with the stars we have here, hopefully they go deep in the playoffs."
But if the Phillies need a guy to get a tough right-handed hitter out late in a game, Kendrick is working his way into the mix.
"I could consider him," manager Charlie Manuel said.
Michael Stutes tossed two scoreless innings, Antonio Bastardo and Brad Lidge worked the eighth, and Ryan Madson finished for his 31st save in 33 chances.
Madson pitched out of a second-and-third, one-out jam by striking out Emilio Bonifacio and getting Omar Infante to foul out.
Placido Polanco got the Phillies started in the first with a one-out single. He went to second on a balk and scored on Hunter Pence's double to left. Raul Ibanez hit an RBI double to right with two outs to make it 2-0.
The Marlins cut it to 2-1 in the fifth on Morrison's 20th homer. Ryan Webb walked Polanco with the bases loaded in the seventh to force in a run that put Philadelphia up 3-1.
The Marlins put two runners on with one out against Bastardo in the eighth. Lidge came in and allowed a single to Gaby Sanchez. But left fielder Ibanez threw out Infante trying to score for the second out.
Lidge then walked Morrison to load the bases. But he struck out John Buck to escape the jam.
Kendrick got plenty of defensive help from second baseman Pete Orr, who made three outstanding plays.
NOTES: Lee reached double digits in strikeouts for the ninth time this season. ... Phillies 2B Chase Utley made his first start in the nightcap since sustaining a concussion last Wednesday. ... The Phillies had two more sellouts, running their consecutive streak to 209, including postseason play. ... The Phillies swept the Marlins in a doubleheader on June 15. ... Sanchez has a 2.25 ERA in his last six starts. ... The Phillies are 28-4 when Brian Schneider is the starting catcher. ... Worley (11-2) takes the mound for the Phillies against Jaime Garcia (12-7) in the opener of a four-game series against St. Louis on Friday night. ... Javier Vazquez (10-11) tries to even his record when the Marlins play at Washington on Friday night.