The Scot went down to the third seed in an at-times testy five-setter in the heat of Flushing Meadows.
The 34-year-old Scot almost defied the odds, the heat, a slippery pair of shoes and some borderline gamesmanship from the Greek world No 3.
But in a match lasting just short of five hours, Murray went down 2-6 6-7 (7) 3-6 6-3 6-4.
Having won the first set – the first he had taken from a top-five player since 2017 – Murray had two points to clinch the second in the tie-break.
But drenched in sweat in the humid conditions, he began complaining that his trainers had become too slippery – yet it soon became apparent he did not have a spare pair.
然而, having come through career-saving hip surgery and a host of other injury problems over the last few years, Murray was not about to let a pair of sweaty pumps derail him.
He took the next set to lead 2-1 but Tsitsipas upped his level, racing 5-0 ahead then taking the match to a deciding set.
When Tsitsipas disappeared for yet another off-court break before the start of the fifth he was given a time violation, but Murray was clearly wound up.
After dropping serve in the opening game he was heard muttering about “cheating” and later asked supervisor Gerry Armstrong why it was taking Tsitsipas so long.
“What’s he doing in there? It’s never taken me that long to go to the toilet,” he moaned.
Feeding off the crowd and a familiar sense of injustice, Murray forced a break point at 1-2 but it was extinguished by a sizzling Tsitsipas forehand.
Tsitsipas held his nerve along the finishing straight and when an exhausted Murray dropped a forehand into the net, his latest Flushing Meadows campaign was over.