Nova tossed a four-hitter and the Chicago White Sox took advantage of an injury to Cole, one of Houston's aces, for a 4-1 win and split of their doubleheader on Tuesday.
Houston won the first game 6-2 behind six solid innings from Zack Greinke in his second start with the Astros and solo home runs by George Springer and Jose Altuve.
Cole, 14-5 with a 2.87 ERA, was listed on the lineup for the nightcap, but the right-hander didn't start after experiencing right hamstring discomfort while he warmed up. He was set to try for his 11th straight win. Instead righty Chris Devenski (2-1) took the mound and lasted just two innings in taking the loss.
"Right before the game, (bullpen coach) Josh Miller called down and told me that his hammy wasn't feeling very good and he didn't feel like he could continue," manager A.J. Hinch said.
Cole went straight to the clubhouse for treatment and will undergo additional tests.
"He doesn't think it's that serious," Hinch said. "We hope that it's mild, but it was literally a couple minutes before the game."
Nova (8-9) limited high-scoring Houston to one unearned run and walked none in his second complete game this season and 10th of his career as he improved to 4-0 with a 0.49 ERA in his last five starts. After hitting Carlos Correa with a pitch in the fourth, the right hander retired 16 straight batters.
"I wish I could pitch like that against everybody," Nova said. "I think I'm locating my pitches better, throwing more strikes.
"But it's the same sequence I always use. I'm just getting good results."
Earlier this season, Nova's pitches were tailing back into the heart of the strike zone. Now they're staying on the fringes.
"He's hitting his spots more," manager Rick Renteria said. "I think he's been executing a lot cleaner recently."
Ryan Goins drove in two runs with a single to cap Chicago's three-run second inning. Ryan Cordell doubled in a run and Adam Engel added an RBI single.
Devenski allowed three runs (one earned) on five hits in his first start of the season and seventh of his career. His error on Cordell's grounder down the first-base line in the second helped set up Chicago's rally.
"Devo did great," Hinch said. "He just didn't field his position."
Three Astros releivers -- Joe Biagini, Hector Rondon and Joe Smith -- followed and allowed one run the rest of the way.
Springer drove in the lone run for the Astros in the second game after connecting on the first pitch of the day then throwing out a runner at the plate from right field in the opener.
Springer said he was ready for an opening fastball from hard-throwing White Sox rookie Dylan Cease. He sent a 467-foot shot to the back of the left field stands.
"The only uncertainty was how hard it was going to be," Springer said. "Obviously, it was going to be anywhere from 94 to 98 (mph). I just decided to swing."
Greinke was close to the form the Astros hoped for when they traded for the right-hander to create an imposing rotation, including Cole.
But he says he still needs to work on a few things.
"My off-speed command was pretty good, but my fastball command is still a work in progress," Greinke said.
Greinke (12-4) allowed two runs on seven hits in winning for the second time since Houston acquired him from Arizona in a deal at the trade deadline. The 35-year-old struck out six, walked two and hit a batter in a 102-pitch outing that was sharper than his Astros debut last week when he allowed five runs in six innings to Colorado.
Will Harris, Ryan Pressly and Collin McHugh each followed Greinke with a perfect inning.
Making his seventh start, Cease (2-5) allowed four runs in six-plus innings. The rookie right-hander yielded five hits and walked five.
Tuesday's straight doubleheader was scheduled after Monday night's game was postponed by rain.
The last team to beat Cole was the White Sox on May 22 in Houston.
INF/OF Myles Straw was recalled from Triple-A Round Rock as Houston's 26th man for the second game and started in center field .RHP Jose Ruiz rejoined the White Sox from Triple-A Charlotte for the nightcap.
Astros: INF Alex Bregman didn't start either game due to a sore shoulder suffered when he was hit by a pitch on Sunday. . RHP Brad Peacock (right shoulder discomfort) was in Houston's clubhouse following two rehab appearances for Triple-A Round Rock and said he felt "really good." Manager A.J. Hinch said Peacock will return to the minors for one or two more outings, starting on Thursday, before rejoining the Astros as a reliever. Peacock was 6-6 with a 4.13 ERA in 17 games (15 starts) before going on the IL on June 28. ... RHP Josh James (sore right shoulder) threw 20 pitches in Florida on Sunday. Hinch said the next step will be to intensify James' rehab program.
White Sox: INF/OF Leury Garcia (bruised finger on right hand) sat out both games. ... Manager Rick Renteria said 3B Yoan Moncada (strained right hamstring) is progressing as he works out with the team, but there's no timetable for his return.
UP NEXT: Astros LHP Wade Miley (11-4, 2.99) faces White Sox LHP Ross Detwiler (1-3, 5.35) in the series finale on Wednesday afternoon. Miley has wins in five straight decisions with a 2.11 ERA in an seven-game span, and has won three straight starts.
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Nova goes the distance in White Sox's win
Ivan Nova pitches a complete game and only gives up four hits and records three strikeouts as the White Sox take down the Astros 4-1 in Game 2 of their doubleheader.