Andy Murray was overpowered by Felix Auger-Aliassime in the US Open second round, losing 6-2 6-3 6-4 in New York.
Murray, 33, came back from two sets down in his first-round match on Tuesday but never threatened to do the same against the 20-year-old Canadian.
He was not able to create a break point against the 15th seed, who hit 52 winners to Murray's nine under the roof on Arthur Ashe Stadium.
Auger-Aliassime will face Britain's Dan Evans or Corentin Moutet next.
The British number one and France's Moutet must finish their second-round match on Friday after heavy rain stopped play on Flushing Meadows' outside courts.
"He got quite a lot of free points with the first serve, and then even when I was getting a racket on it he was able to dictate off the first shot of the rally," said Murray.
"Physically, I actually did pretty well I thought in the first round. But I think the more tournaments that you play, the more matches that you play, you build up that sort of robustness in your body which right now I don't really have."
Although this defeat was very one-sided, Murray can take plenty of positives from the past two weeks at Flushing Meadows, having won two matches at the Western and Southern Open before coming from two sets and a break down to overcome Nishioka on Tuesday.
That victory was his first Grand Slam singles match since a career-saving hip resurfacing operation in January 2019. After returning in doubles, he missed last year's US Open to focus on his singles return and was then ruled out of January's Australian Open with a pelvic injury.
Given all that, it was a monumental effort to win in nearly four hours and 40 minutes against Nishioka but the effect was apparent in Thursday's night session as Murray struggled to live with Auger-Aliassime's dazzling array of shots.
The Canadian completely dominated the first set, dictating play from the baseline and hitting 18 winners to Murray's one.
Murray was more competitive in the second set but Auger-Aliassime broke in the eighth game and an ace gave him a two-set lead.
He then converted his fourth break point in the fifth game of the final set and while Murray kept fighting, he only delayed the inevitable with the Canadian serving out the win to love.
Murray will now turn his attention to the clay and preparing for the delayed French Open, which is due to start on 27 September at Roland Garros.
Meanwhile, Dominic Thiem comfortably progressed to the US Open third round, beating India's Sumit Nagal 6-3 6-3 6-2.
The Austrian second seed, celebrating his 27th birthday, will next face 2014 champion Marin Cilic, who overcame Norbert Gombos 6-3 1-6 7-6 (7-2) 7-5.
There was a surprise as Vasek Pospisil knocked out fellow Canadian Milos Raonic 6-7 (1-7) 6-3 7-6 (7-4) 6-3.
Raonic, the 2016 Wimbledon finalist and seeded 24th, defeated Andy Murray at last week's Western and Southern Open.
World number 94 Pospisil will now play Spanish eighth seed Roberto Bautista Agut, who defeated Serb Miomir Kecmanovic 6-3 3-6 6-3 6-4 at Flushing Meadows.
Last year's finalist Daniil Medvedev, seeded third, had a straightforward 6-3 6-2 6-4 win over Christopher O'Connell.
Grigor Dimitrov, who reached the semi-finals in New York last year, lost 6-7 (5-7) 7-6 (7-4) 3-6 6-4 6-1 to Hungary's Marton Fucsovics.
Fucsovics next faces American Frances Tiafoe who beat Australia's John Millman 7-6 (8-6) 3-6 1-6 6-3 6-3.
Italian sixth seed Matteo Berrettini moved past Frenchman Ugo Humbert 6-4 6-4 7-6 (8-6) and will play Norway's 30th seed Casper Ruud.