The Phils blew a chance to come away with a split when their bullpen squandered a 4-2 lead late, as the Astros scored four runs in a decisive seventh inning.
When the inning began, it looked like Philadelphia would pad its 4-3 edge.
Chase Utley sent a long drive to right field that looked like it would go over the head of Houston's Jimmy Paredes and score Michael Martinez, who doubled, and possibly pinch-hitter Ty Wigginton, who was hit by a pitch, as well.
But Paredes made a leaping catch to rob Utley of extra bases. He then played a role in sparking the Astros' rally in the bottom half of the inning.
Paredes walked after Jose Altuve reached on what was ruled an error on Martinez, who made a sparkling grab behind third base of Altuve's liner. But Martinez's throw was in the dirt and past first baseman Ryan Howard.
The game turned at that point, with Houston's Justin Maxwell hitting a go-ahead two-run double and Matt Dominguez following with a two-run single to make it a 7-4 game. Maxwell's blooper raised chalk down the right-field line before Dominguez bounced a chopper past a drawn in infield.
"It was a tough inning," Manuel said. "We felt like we had a chance to score some runs, and we didn't. And all of a sudden, they go right back out there and we make a throwing error and all [heck] breaks loose."
The Phillies took a 4-2 lead with a three-run fifth inning, highlighted by a two-run double from Howard. It was the 200th career double for the Phils' cleanup hitter, who has driven in 36 runs over the last 37 games.
Credit leadoff hitter Jimmy Rollins for starting the two-out rally with a single. Rollins was 3-for-4 with two singles, a double, a walk and two runs scored. In addition, Rollins stole his 30th base of the season, marking his 10th 30-steal campaign.
Phillies starter Roy Halladay worked six innings, striking out seven while yielding six hits, two walks and three earned runs. He handed a one-run lead to the bullpen.
"Halladay's a tough pitcher," Maxwell said. "He really hits his spots and he throws any pitch in any count. Sometimes, you get lucky."
Halladay has not had a losing decision in his last six starts, going 4-0 with a 4.70 ERA over that span.
"We had a couple of chances to win," Halladay said. "But we came up short. We move on, and hopefully go after the Mets."
Halladay gave up homers to Scott Moore and Carlos Corporan.
"It's kind of an odd team to pitch to," Halladay said. "Sometimes they're aggressive, sometimes they're not. I think the whole series, we never really figured out what their plan was. That made it tough.
"They come up swinging at a lot of first pitches. And then they take until two strikes. It was not a lot of pattern. It's kind of tough as a pitcher to figure it out."
Manuel said he saw a free-swinging team that took advantage of nearly every opportunity over the four games.
"They're loose and they're swinging the bat and hitting the ball," he said. "They've been getting their hits, finding the holes. They wear a Major League uniform, they swing the bat pretty good.
"I don't know what to say, except that you've got to give them credit. They hung in there and they got the right hits and they made the right plays at the right time. [Paredes] makes the play on Utley's ball, what can you say. We got two runs there for sure [if he doesn't catch it]."
Sunday's loss marked the first time the Phillies have lost consecutive games since dropping two to the Mets, Aug. 28-29.
"Losing three out of four here really hurts," Manuel said. "But we've still got to keep playing. It's kind of how we got into it, just keep on playing."