Michael Young and Domonic Brown homered for the Phillies, and Erik Kratz singled in the tiebreaking run in the seventh inning to snap Boston's four-game winning streak.
Lee (6-2) allowed a first-inning run and then retired 22 of the next 23 batters to win his fourth consecutive decision. He struck out eight to match his season high and walked none.
Ryan Dempster (2-6) allowed two runs on six hits and three walks, striking out four in seven innings for Boston.
Papelbon pitched a perfect ninth for his 10th save. The Red Sox closer from 2005-11 - including their 2007 World Series title - he entered to a chorus of boos and without the theme song "Shipping up to Boston" he used for much of his career here.
But he retired the Red Sox in order, pumping his fist in celebration after getting David Ortiz on a grounder to the right side of the shifted infield to end the game.
That was all the support Lee needed on a night when he again helped the Phillies stop a losing streak. Philadelphia had lost two straight, including Monday night's 9-3 Red Sox victory in the opener of the two-game interleague series.
Lee is 5-1 this season in eight starts following a Phillies loss. The teams now head to Philadelphia for a two-game series at Citizens Bank Park.
Young cleared the Green Monster in the top of the first, but the Red Sox tied it when Jacoby Ellsbury led off the bottom half with a single, stole second and then scored on Dustin Pedroia's single.
Both pitchers settled down, and it was still 1-all when John Mayberry Jr. singled to lead off the seventh, Freddy Galvis bunted him to second and Kratz singled him home.
Meanwhile, the only baserunner Lee allowed from the first inning to the eighth was Daniel Nava on a leadoff single in the fifth. Ortiz did make a 415-foot out in the fourth when Ben Revere chased down his deep fly ball in Fenway's center field triangle; he also hit a high fly just to the foul side of the Pesky Pole in the ninth against Papelbon.
NOTES: Lee has not issued a walk in 77 of 291 career starts. ... Dempster needed 60 pitches to get through four innings and left after throwing 98 in all. ... Ryan Howard struck out swinging in each of his first two at-bats. He singled through the shift in the sixth inning to put runners on first and second with one out, but Delmon Young and Brown each flied out to right field. ... The Red Sox activated LHP Franklin Morales from the disabled list and optioned Alfredo Aceves, Monday's winner, to Triple-A Pawtucket. ... Boston Marathon bombing victim Jeff Bauman and his rescuer, Carlos Arredondo, took part in the first pitch ceremony.