On a day when two more men retired from their matches -- pushing the four-day male total to 12, a Grand Slam record in the Open era -- Murray spent 3 hours, 17 minutes in the cauldron of Arthur Ashe Stadium.
In a challenging first-round match, Murray beat Aussie bad boy Nick Kyrgios with patience and relentless defense. In the second, Murray needed to master his emotions -- and what looked to be mild cramping -- to book a Saturday encounter with No. 30 seed Thomaz Bellucci.
"I just had to kind of tell myself that I would get there eventually," Murray said. "I had time to get back into it."
Murray has not lost in the second round of the US Open since his first appearance in 2005. Three years later, he advanced to the final, falling to Roger Federer, who won his fifth straight title. Four years after that, Murray won his first and only championship at Flushing Meadows, beating Novak Djokovic in the final.
For the first two sets Thursday, though, it wasn't about Murray at all. Mannarino, who hits unusually flat shots, struck 30 winners against 15 unforced errors and broke Murray's formidable serve three times while saving 7 of 8 break opportunities.
"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."
Murray came back, winning 18 of the match's final 23 games, to improve to 21-1 in the first two rounds of the tournament all-time.
"He was looking for his rhythm," Mannarino said, "and then I think that finally he found it."
Wawrinka had 26 aces and 62 winners but a whopping 66 unforced errors against Hyeon, a South Korean who is ranked 69th. Wawrinka will face Ruben Bemelmans in the third round.
John Isner also swept through to the third round, defeating Mikhail Youzhny 6-3, 6-4, 6-4, and Donald Young rallied to win again, this time from a set down to beat Aljaz Bedene after erasing a two-set deficit to knock off Gilles Simon in his opener Tuesday.
Lleyton Hewitt's final US Open came to a close as well. The 2001 champ rallied from two sets down and had a pair of match points but wasn't able to complete the comeback, losing to fellow Australian Bernard Tomic 6-3, 6-2, 3-6, 5-7, 7-5 in almost 3½ hours.
Hewitt plans to retire after the Australian Open. He considers himself a mentor to Tomic, who is seeded 24th, and didn't look forward to playing him.
"He's a huge legend for me," Tomic said in an on-court interview. "I've always looked up to him. It was difficult for me playing him tonight."
ESPN's Greg Garber and The Associated Press contributed to this report.