Murray, after all, is seeded No. 3, owns two major championships including at Flushing Meadows in 2012, and had reached at least the quarterfinals at the last 18 Grand Slam tournaments he'd entered. Mannarino, meanwhile, is ranked 35th, has never won a tour-level title, and only three times in his career has even managed to win more than one match at a major.
So it certainly came as a surprise when, in Thursday's opening game, Mannarino broke Murray. About an hour later, Mannarino grabbed the opening set. And 45 minutes after that, the Frenchman took the second set, too.
"I just had to kind of tell myself that I would get there eventually," Murray said. "I had time to get back into it."
Despite a stuffy nose and scratchy throat, and generally looking as if he might be ready to wilt on another steamy day at Flushing Meadows — two more mid-match retirements, including by 28th-seeded Jack Sock of the United States, raised the total to 12 in the men's draw so far — Murray put together his eighth career comeback from a two-set deficit and beat Mannarino 5-7, 4-6, 6-1, 6-3, 6-1.
"He was looking for his rhythm," Mannarino said, "and then I think that finally he found it."
Roger Federer had his rhythm from the start, compiling a 46-8 edge in winners while beating Steve Darcis of Belgium 6-1, 6-2, 6-1 at night, before 2014 runner-up Caroline Wozniacki was stunned by 149th-ranked Petra Cetkovska of the Czech Republic 6-4, 5-7, 7-6 (1) in the day's last match, which ended after midnight. Wozniacki held four match points but each was erased by a winner from Cetkovska.
Against Murray, Mannarino, a lefty, delivered 12 of the match's first 14 forehand winners and repeatedly found success with drop shots.
But his play eventually dipped, while Murray really cleaned up his own act after the rough start: He went from making 21 unforced errors in the first two sets to only 14 the rest of the way.
"He has such an unorthodox game, I didn't really feel that comfortable at many points," Murray said. "But I was happy, very happy, with the way I fought through that, finished the match stronger than him."
Early in the fourth set, Murray doubled over and rested his hands on his knees after a couple of points, the sort of thing the Brit has been known to do during matches — appearing weary or injured yet able to still play well.
"Who knows? Maybe he (is) — not faking — but sometimes (feeling) tired, even if he's not," Mannarino said.
"That's, I think, what a lot of people do when they're out of breath or tired," he said.
Sock took the opening two sets against 107th-ranked Ruben Bemelmans of Belgium and was three games away from winning in the third, but his body seized up because of cramps, unable to deal with the heat that topped 90 degrees.
In a scary scene early in the fourth set, less than two hours in, Sock froze in place, his legs locked. A trainer helped the 22-year-old American sit down near the baseline, and Sock appeared to have trouble even extending his arm when Bemelmans walked around the net and leaned over for a handshake.
"I didn't have too much difficulty," said Bemelmans, who will face French Open champion Stan Wawrinka next.
Sock didn't hold a news conference, instead releasing a statement that called his retirement "extremely disappointing."
"It's tough to see," Isner said about Sock's cramping. "It's not a fitness thing. I think that's a big, big misconception. He's in very good shape. He can play 50-ball rallies if he wants to. But he sweats a lot. ... His body was at a deficit of whatever it is — sodium, magnesium, potassium."
Denis Istomin of Uzbekistan stopped playing against 20th-seeded Dominic Thiem of Austria, citing an injured right leg.
Including two retirements by women, 14 players have stopped playing during matches because of injury or illness, tying the 2011 U.S. Open for the most through the first two rounds at a Grand Slam tournament.
"Maybe it's the end of the year — players are not as fit ... as in the beginning of the year," Bemelmans said. "It's the humidity, the heat — it's all these combinations."