Andy Murray suffered his earliest Grand Slam exit for five years as he lost a gruelling fourth-round contest against 15th seed Kevin Anderson.
The South African won 7-6 (7-5) 6-3 6-7 (2-7) 7-6 (7-0) in four hours and 18 minutes to reach a first major quarter-final, where he faces Stan Wawrinka.
It is the first time since the 2010 US Open that Murray has lost before the quarter-finals of a Grand Slam.
Briton Jo Konta lost 7-5 6-3 to Petra Kvitova in the women's singles.
A gripping evening at Flushing Meadows saw Britain's two remaining singles hopes exit within 12 minutes of each other.
While Konta's 16-match winning run ended in straight sets in the cavernous Arthur Ashe Stadium, Murray's hopes disappeared in a fever-pitch atmosphere on Louis Armstrong Stadium.
An emotional Murray smashed his racquet - handing it over to a spectator - and argued with the umpire before launching a fightback in the third set, but Anderson dominated the decisive tie-break.
It is 38 years since Britain had male and female quarter-finalists at the same Grand Slam, but Murray's defeat means it is the first time in five years there have been neither.
"That's obviously something that is disappointing to lose," Murray said after a run of 18 Grand Slams in which he made at least the quarter-finals.
"Obviously that's many years' work that's gone into building that sort of consistency. To lose that is tough."
Anderson will play Stan Wawrinka in the last eight
At 6ft 8in tall and with a chart-topping 69 aces heading into the match, there was no mystery to the South African's greatest strength - his serve.
In five of their past six encounters, including the Queen's Club final in June, Murray's returning had proved more than its equal.
However it took until he was a set and 5-1 down for the Scot to break serve this time, and Anderson saw off another break point to clinch the set at the second opportunity.
The South African then left the court for six minutes, prompting an angry outburst from Murray towards umpire Jake Garner as he asked "what's reasonable?" for such an interruption.
Murray's mood did not lighten when Anderson moved a break up at the start of the third, but it galvanised the Scot to play his best tennis of the match in a burst of three games in a row.
However Murray then put a forehand wide to give the break straight back and duly took out his frustration on his racquet.
It came down to another tie-break and this time Murray made the running, moving 6-2 clear and sealing it with an ace before pumping his fist in the direction of his team and the spectators.
He had already recovered from two sets down against Adrian Mannarino in round two, but Anderson proved much tougher.
The world number 14 had let a similar lead slip against Novak Djokovic at Wimbledon but remained rock solid this time, pushing for the break before completely dominating the third tie-break of the match.
He raced into a 6-0 lead and converted his first match point for the biggest win of his life, in the longest match of this year's tournament.
Murray was frustrated throughout the match and took his anger out on his racquet
The Briton has had his struggles in the past on the second show court at Flushing Meadows, notably the 2010 defeat by Wawrinka in the third round.
He also suffered a potentially tournament-ending bout of cramp there against Robin Haase last year, and fell 6-3 5-1 down to Marin Cilic in what would be his title-winning run of 2012.
"Obviously I had some tough losses there, some tough matches," said Murray. "But I've also had some good wins on that court, as well.
"But it's tricky. I've been playing on Ashe. Armstrong is a tighter court which is very open. You get a lot of wind in there. It's different conditions and something you need to just try and adjust to."