"I was looking changeup," said Brown, "It was the only fastball I had seen from him in three at-bats. So I was just trying hit something in the middle the other way and I just reacted to the ball.
"I just wanted to keep the swing short and quick and made that adjustment."
Marquis (9-3), who had won eight straight decisions over his past 11 starts, went 4 1/3 innings, giving up six runs on six hits, walking five and striking out four to take the loss.
"It was a fastball, up and out over the plate," Marquis said of the pitch Brown hit out. "It's 2-0 -- a hitter's count -- and he put the barrel on the ball."
He allowed back-to-back walks on eight pitches to Ryan Howard and Brown in the fifth inning, which led to Marquis' exit from the game and contributed to three more runs by the Phillies, who took their 6-2 lead.
Marquis, who hadn't lost a game since April 22 against Milwaukee, leads the majors in walks with 53. He has had four or more walks in 11 of his 16 starts.
The Padres have lost five of eight since a season-high seven-game win streak.
Kyle Kendrick (7-4) went eight innings for Philadelphia, allowing two runs on seven hits with six strikeouts and no walks to pick up the victory.
"It's always nice to pitch eight innings," said Kendrick. "That was a good win for us. I was throwing my cutter a lot more than usual tonight. That home run by Brown was big particularly after we gave up two and to come back and take the lead."
Brown, who walked with the bases-loaded in the fifth to drive in a run, had hit a three-run homer off Marquis in the third for a 3-2 lead.
Rollins walked to lead off the third and stole second. He went to third on a one-out single by Michael Young.
Marquis struck out Howard, but Brown hit a 2-0 pitch 411 feet into the right-center-field stands. He is second in the NL in homers, one behind Carlos Gonzalez. It was his first homer since June 8, a span of 56 at-bats. He has 54 RBIs.
The Padres threatened in the ninth on Grandal's single and Ciriaco's third hit of the game, a double. But reliever Antonio Bastardo struck out Logan Forsythe for the final out.
Padres LHP Robbie Erlin (1-0, 4.15 ERA) will be called up from Triple-A Tucson on Wednesday and will make his second major league start against Philadelphia. "We like we saw when he beat the Blue Jays. He's getting to a point where he's about to break through," said Padres manager Bud Black. LHP Cole Hamels (2-11, 4.50 ERA) will pitch for the Phillies in the final game of the series. ... Padres 2B Jedd Gyorko on the DL with a right groin strain, flew to San Antonio on Tuesday and will play with the Padres Double-A team Wednesday and Thursday. If all goes well, according to Black, Gyorko would be activated and would join the team Friday in Miami. ... Padres 3B Chase Headley batted cleanup Tuesday for the second straight day. However, Black said he will likely not stay there even if he heats up. "We were hoping a different look would give him a different perspective on the game. I don't think it had anything to do with him getting two hits (on Monday)." ... Phillies 1B Ryan Howard returned to the starting lineup after sitting out Monday's game with a sore left knee. Howard was batting .432 over his past 12 games with three home runs and 11 RBIs. ... Phillies RHP Carlos Zambrano is scheduled to make another start at Triple-A Lehigh Valley on Friday before the club makes a decision whether to call him up. Zambrano, who last pitched in the majors for the Miami Marlins in 2012, is 1-0 in three starts with Lehigh Valley with a 3.18 ERA, 17 strikeouts and nine walks in 16 innings.
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SAN DIEGO, CA - JUNE 25: Domonic Brown #9 of the Philadelphia Phillies hits a three-run homer during the third...