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Australian men's No.1 Alex de Minaur is out of the US Open after a first-round loss to American Taylor Fritz.

Still recovering from COVID-19, a dejected Alex de Minaur admits he's down on confidence after making a first-round exit from the US Open.

The Australian men's No.1 was forced to withdraw from the Olympics after contracting the virus and has only managed to get past the first round once since, meaning he's only played four matches since his first-round loss at Wimbledon in June.

A lacklustre de Minaur looked out of sorts for much of his meeting with big-serving American Taylor Fritz late Tuesday night in New York, going down 7-6 (7-4) 6-2 1-6 6-4.

The world No.17 hadn't dropped a set to big-serving Fritz, ranked 25 places below, in their previous three ATP Tour meetings.

A quarter-finalist in 2020 before losing to eventual US Open champion Dominic Thiem, de Minaur entered the tournament with his highest grand slam seeding at 14.

But he said he was still finding his way back mentally, as well as physically, from COVID-19.

"I still haven't felt myself, I haven't played the way I wanted to play so it's very disappointing," the 22-year-old said.

"There's two factors there - there's physical and a confidence factor and my results the last couple of weeks haven't really helped.

"I'm trying to get back to my old self and hopefully it will come sooner rather than later."

With 49 unforced errors and converting just four of 13 break points, de Minaur was a shadow of his usual energised self in the second set and trailed 0-5 before making a mark.

While he didn't challenge for the set it seemed to spark a revival, while Fritz went off the boil for the Australian to steam through the fourth.

The two went toe to toe in the fourth before Fritz broke de Minaur to wrap up the win, to notch his first top-20 scalp at a major tournament.

De Minaur said the 23-year-old American deserved the win.

Fritz has some form, pushing world No.1 Novak Djokovic to a five-set thriller in the third round of this year's Australian Open.

"I think today it wasn't a matter of post COVID or anything like that, and I think it was a high-level match and Taylor played better in the big moments," de Minaur said.

"I didn't take my opportunities, he deserved to win, he was the better guy out there."

He's set to dip out of the world's top 20 after failing to protect his ranking points after his quarter-finals appearance last year.