It was a hugely disappointing way for Murray to mark the 10th anniversary of his career-defining first Wimbledon title, and he is all too aware his chances for another deep run here are ebbing away.
The match began under the roof on Thursday but there were blue skies above on the hottest day of the tournament as Murray returned two sets to one up.
Murray had clearly been eager to avoid the lottery of another tie-break and, in a repeat of the first-set shoot-out, it was Tsitsipas who won the final four points.
Murray’s strategy to relentlessly probe the Greek’s backhand was perhaps becoming a little predictable, and he was in serious trouble when Tsitsipas created three break points in the third game of the deciding set, taking the third to break serve for the first time.
The home favourite saved two match points but Tsitsipas clinched it on his third chance with his 17th ace to book a third-round clash with Laslo Djere.
There was more disappointment for local fans when last year’s semi-finalist Cameron Norrie also got knocked out, beaten 6-3 3-6 6-2 7-6 (7-3) by American Christopher Eubanks.
Liam Broady was the only British man to make the third round but his singles campaign ended 90 minutes after Norrie’s with a 4-6 6-2 7-5 7-5 loss to Denis Shapovalov.
He took no comfort from going the furthest, saying: “It kind of makes it worse that we’ve all lost on the same day.
“Obviously I’d have preferred for us all to have won. Probably would have felt a bit better if we’d staggered what days we lost on, whereas now it’s a bit of a Debbie Downer, isn’t it?”
World No.1 Carlos Alcaraz had earlier had to work hard for his first Centre Court win, earning a 6-4 7-6 (7-2) 6-3 second-round victory over Alexandre Muller.
It made it seven consecutive wins on grass for the top seed, who is viewed by many as the most likely candidate to stop defending champion Djokovic in his pursuit of a record-equalling eighth title at the All England Club.
“Of course, it’s really special … A really beautiful court,” said Alcaraz. “I feel that I belong in that court. It would be amazing for me play a final here in Wimbledon. Even better if is against Novak, obviously.”
Alcaraz made 41 unforced errors and did not have it all his own way against an obstinate opponent, who clearly enjoyed his first outing on the big stage.
No.3 seed Daniil Medvedev was impressive in a 6-3 6-3 7-6 (7-5) win over the dangerous Frenchman Adrian Mannarino.
Olympic champion Alexander Zverev defeated Yosuke Watanuki 6-4 5-7 6-2 6-2 and will face Matteo Berrettini, who hammered Alex de Minaur in straight sets.
Last year’s quarter-finalist Jannik Sinner beat unseeded Frenchman Quentin Halys 3-6 6-2 6-3 6-4.
Defending men’s champion Novak Djokovic has blitzed Stan Wawrinka off the court to advance at SW19, while another Wimbledon dream is over for Andy Murray.
Novak Djokovic was in a hurry, beating both Stan Wawrinka and the Wimbledon curfew to book his place in the fourth round.
The match began an hour later than the previous night when Andy Murray and Stefanos Tsitsipas got under way, but Djokovic finished a 6-3 6-1 7-6 (7-5) victory with 14 minutes to spare.
It certainly did Wawrinka no favours that Djokovic was against the clock as he clicked straight into top gear and pushed the pace at every opportunity.
Djokovic pounded precision groundstrokes into the corners, time and again drawing errors from his opponent after thumping exchanges.
It was a 31st consecutive victory for the Serb at the All England Club, equalling Pete Sampras’ best, and the seven-time champion said: “He was two points away from extending this match to another day. Coming to the court we knew it was going to be really tight.
“I know I can always play better, I always have a couple of gears that I can go higher. Hopefully as the tournament progresses I can play better and better.”
Murray, earlier, suffered more Wimbledon heartache with a five-set defeat to Tsitsipas in their delayed second-round clash to mark a day of misery for local fans.
The Scot was two sets to one up overnight when the 11pm curfew came into play but he was unable to complete the job, with fifth seed Tsitsipas fighting back to win 7-6 (7-3) 6-7 (2-7) 4-6 7-6 (7-3) 6-4 on Friday.
