Suffering an ignominious defeat to South African Kevin Anderson in four sets, Murray looked frustrated and often powerless against the 15th seed who played out of his skin.
Anderson took the game 7-6, 6-3, 6-7, 7-6.
Murray, the World No. 3, complained to himself and the umpire repeatedly -- often in expletive-laden tirades caught on camera -- about everything from perceived game delays by Anderson to line calls.
The truth is, it just wasn't his day.
Going into the match, the 29-year-old Anderson was an unlikely candidate to dominate a former U.S. Open and Wimbledon champion.
In his ninth year on the pro circuit, Anderson has had only three tour victories to his name and never advanced beyond the fourth round at a Grand Slam.
But the 6'8' Johannesburg native was a force throughout the match, battling nerves only occasionally. He was broken early in the third set before losing it on a tiebreak, before coming back with an assured performance in the fourth set.
Anderson played aggressively and took chances, pouring 25 aces past a sometimes helpless Murray, who was denied a 20th consecutive Grand Slam quarterfinal run.
He hit 81 winners during the match against Murray's 49, and rushed the net 58 times versus 24 approaches for Murray. In fact, Anderson has been the most prolific net player in the entire U.S. Open, often displaying a graceful touch belying his giant frame.
'I'm a little lost for words right now. I was just trying to keep my composure against Andy, and I honestly played one of the best matches of my life,' said Anderson, who clinched the fourth set tiebreak to win.
'He's such a fighter, and such an amazing player, I knew I had to try my best and just stick with it,' he said.
Federer raises game to down Isner
World No. 2 Roger Federer faced No. 13 seed John Isner in the late match in Arthur Ashe Stadium, ultimately handling the big American's serve in three tight sets, winning the match 7-6, 7-6, 7-5. The Swiss player made his way to the quarterfinals for the 11th time with a vintage Federer performance, keeping alive his hopes of raising the trophy at Flushing Meadows for a sixth time.
Federer kept his nerve throughout, not losing his serve to Isner once. For his part, Isner fought back gamely, only losing his serve once at the very end, and taking nine break points away from the winner. However, he was not able to match his 2011 U.S. Open-best quarterfinal result.
Obviously John has one of the best serves in the game,' Federer said after the win. 'You just gotta hang around and make sure you don't drop your serve.'
The 34-year-old, 17-time Grand Slam men's singles champion has been on form throughout the summer, climbing back up the rankings to breathe down world number one Novak Djokovic. He's next set to play 12 seed Richard Gasquet in the quarterfinals.
Temperatures soared once again on the hard courts of Flushing Meadow in a competitive, and sometimes quirky, eighth day of action at the U.S. Open.
French Open champion Stan Wawrinka took four sets to cruise past American upstart Donald Young, in a match that saw a bizarre build-up.
Young -- who had battled back from two sets down in his previous two matches at the Open -- had his locker mistakenly cleared out the day before the match, leaving him scrambling to find equipment until shortly before the match.
'Unfortunately, I came to the locker room yesterday and I opened it up and it was clean,' said Young, a former junior World No 1. 'Like a couple shirts missing, all my shoes were gone, and apparently someone said I was out of the tournament, so the guys thought I went home. They were taking some souvenirs.'
Young showed some signs of life, taking the second set from Warwinka 6-1, before dropping the third and fourth sets.
Warwinka will face Anderson in an intriguing quarterfinal matchup.
Meanwhile, Victoria Azarenka of Belarus, who opened play in Arthur Ashe Stadium on Monday, took just under one hour to knock out her fourth round opponent American Varvara Lepchenko, in straight sets.
Twentieth seed Azarenka will face Simona Halep, the No. 2 seed from Romania, in the quarterfinal. Halep defeated power-serving German Sabine Lisicki in a tense three-setter which saw a 10-minute heat break between the second and third sets.
Halep was quick to point out that it was her opponent who called for a break, although she certainly didn't mind the breather. The temperature in New York -- which consistently topped 32˚C (90˚F) last week -- touched 33˚C (92˚F) on Monday.
'I was fighting till the end. I did everything I could to win the match,' said Halep, who, though visibly elated, added that she had a mixed doubles match scheduled for later in the day. 'I'm tired, I can say.'
The first round of this year's U.S. Open witnessed a record 12 withdrawals, reigniting speculation that hard courts are more punishing on tennis players than clay and grass surfaces.
A leading sports physicist claimed before Wimbledon that grass was significantly cooler than hard courts on a hot day, which -- along with less grip on the surface -- explained the relatively low number of Wimbledon withdrawals versus those in the U.S. Open and the Australian Open over the years.
'On a hot day like 40˚C (104˚F), the temperature on the court itself can be 60˚C (140˚F). If you took your shoes off you'd actually burn the skin off your feet,' said Professor Rod Cross from Sydney University. 'That's physically exhausting and I think it's crazy to have courts that are so hot.'
Last week, American Jack Sock fainted on the court, leading to a forfeiture of his second round match.
New Yorkers are expected to face more warm weather on Tuesday before temperatures cool off over the rest of the week.
Meanwhile, another Grand Slam chapter of the somewhat lacklustre head-to head series of Williams sisters battles is set to take place in a quarterfinal match on Tuesday.
Serena Williams will face her sister, No. 23 seed Venus Williams, in a rematch of their fourth round match at Wimbledon. Serena won that match 6-4 6-3, on her way to winning her sixth Wimbledon title.
Serena is vying for her first career calendar Grand Slam, having won all three of the previous majors in 2015. No female player has achieved the feat since Steffi Graf in 1988.
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