Howard singled in the winning run with two outs in the bottom of the 15th inning to lift the Philadelphia Phillies to a 2-1 victory over Houston on Tuesday night.
The interleague matchup between teams with two of the four worst records in the majors lasted 5 hours, 5 minutes.
Hector Neris (1-0) tossed a perfect inning to earn the win in his major league debut.
Grady Sizemore led off the inning against Jake Buchanan (1-2) with a hard one-hop single under second baseman Jose Altuve's glove. After Ben Revere sacrificed, Jimmy Rollins flied out and Chase Utley was intentionally walked.
Howard then ripped a 1-2 pitch to right and Sizemore slid in safely ahead of right fielder Robbie Grossman's throw.
"You go up there with a chip on your shoulder," Howard said. "Them walking Chase, I wanted to get it done."
It was the fifth game of at least 14 innings for the Phillies this season, tying a franchise-record first set in 1958.
Howard led off the bottom of the second with an opposite-field homer that just cleared the wall in left-center, giving the Phillies a 1-0 lead. The run snapped a 22-inning scoreless streak for Philadelphia, which was shut out in Washington on Saturday and Sunday.
Howard's homer was his seventh off lefties in 97 at-bats. He has only 10 against right-handers in 308 at-bats. Howard, who faces an extreme shift to right in all of his at-bats, still hasn't pulled a homer.
The struggling slugger is batting just .217 and was benched three straight games last month.
"You guys forget what I've done," the former NL MVP said. "People look at right now. I've hit balls hard over stretches. All you can do is hit balls hard and once it leaves the bat, it's out of your hands."
Jon Singleton's RBI single in the seventh tied it at 1. The Astros had runners at first and third with no out, but couldn't get the go-ahead run. Matt Dominguez flied out to shallow right and Jake Marisnick grounded into a double play.
"A really tough game," Astros manager Bo Porter said. "We just couldn't get the offense going."
Astros: Outfielder George Springer, on the disabled list since July 20 with a strained left quad, made his second rehab appearance at Single-A Quad Cities. Springer could be called up before the series ends Thursday.
Astros: Right-hander Brad Peacock (3-7, 4.93) will come up from Triple-A Oklahoma City to start Wednesday night. He's replacing Jarred Cosart, who was traded to Miami last week. Peacock gave up seven runs in 3 2/3 innings in his last start on July 23, a 9-7 loss at Oakland.
Phillies: Righty David Buchanan (5-5, 4.40) will be recalled from Triple-A Lehigh Valley to take Lee's spot. Buchanan has allowed three earned runs or less in his last six major-league starts
Keuchel (10-7) has allowed just two earned runs in his last three starts, but is only 1-1 in that span. The lefty lowered his ERA to 2.89.
Kendrick remained 5-11 after giving up five hits in his first quality start in six outings since July 3. Kendrick lowered his ERA to 4.74.
HUNTER PENCE HAUNTS
The Phillies acquired Pence, an All-Star outfielder, from the Astros on July 29, 2011 for Singleton, Cosart, outfielder Domingo Santana and right-hander Josh Zeid. They were 50-30 at the time and finished with a club-record 102 wins before losing to St. Louis in the NLDS.
Clearly, the Astros and Giants were big winners in both trades with the Phillies.
SAVE THAT BALL
Santana walked with two outs in the 10th, reaching safely for the first time in his career on his 22nd birthday. He was 0 for 13 with 11 strikeouts before drawing a walk.
Phillies lefty Antonio Bastardo struck out six of the seven batters he faced in the 11th and 12th innings and the Astros fanned a season-high 17 times.