It was not immediately known whether Cole will miss additional time. Cole began warming up in the Astros' bullpen before reporting right hamstring tenderness.
"Right before the game, as he was warming up, [bullpen coach] Josh Miller called down and told the dugout that his hammy wasn't feeling very good, and he didn't feel like he could continue," Astros manager A.J. Hinch said.
Cole was replaced as the Astros' starter by reliever Chris Devenski.
"[Devenski] was on his way out to the 'pen," Hinch said. "He's usually the first reliever out there anyway, so we raced to get him ready."
Cole underwent treatment during the game and will undergo further examination on Wednesday. Hinch is hopeful that the injury is minor -- and glad Cole was forthright in his communication with the club.
"We'll get him tested even further and see where this takes us," Hinch said. "He doesn't think it's that serious. I'm glad he told us, and we hope that it's mild. It was literally a couple of minutes before the game."
Cole wasn't available for comment after the game.
Cole, 28, is tied with Justin Verlander for most starts (25) this season for Houston and ranks second to Verlander with 156⅔ innings pitched. He's 14-5 with a 2.87 ERA and an AL-leading 226 strikeouts.
The Astros lost the nightcap 4-1 after winning the first game 6-2. With Cole unable to pitch, Houston used four relievers, beginning with Devenski, to navigate the contest. That included a three-inning outing by righty Joe Biagini, who was optioned to Triple-A Round Rock after the game. Suddenly, Houston is in need of fresh arms.
"A doubleheader will do that to you in general," Hinch said. "[Then] you lose your starter five minutes before the game."