James Duckworth has suffered a crushing five-set defeat to join fellow Australians John Millman and Astra Sharma out the US Open exit gates.

Duckworth blew four match points in the third-set tiebreaker before succumbing 4-6, 4-6, 7-6 (9-7), 6-2, 6-2 to Spain's Pedro Martinez.

But the news was better for Alexei Popyrin, who became the first Aussie through with a 6-3 6-7 (3-7) 6-3 6-3 victory over Radu Albot.

Millman earlier slumped to a 7-6 (8-6) 7-6 (7-2) 6-1 first-round loss to Swiss qualifier Henri Laaksonen on day one at Flushing Meadows, while Sharma lost 6-0 6-3 to eighth-seeded French Open champion Barbora Krejcikova.

Millman's early departure comes three years after the Queenslander slayed five-times champion Roger Federer en route to the quarter-finals in New York

But the veteran's defeat, after entering the season's final grand slam under a fitness cloud, was nothing on Duckworth's gut-wrencher.

After hitting a career-high number 67 in the rankings last week, Duckworth was well on his way to continuing his watershed season before letting his huge opportunity slip.

The Sydneysider led 6-3 in the crucial breaker and then relinquished the fourth set in quick fashion to find himself fighting against the momentum.

He composed himself to gain an early break in the fifth only to concede six games straight to bow out after a tense and marathon affair stretching four hours 20 minutes.

Enjoying a breakout run to the Wimbledon third round last month, and also making round two at Roland Garros and Melbourne Park, Duckworth had been bidding to win matches at the four majors in the same year for the first time in his injury-plagued career.

There was also disappointment for Sharma, who was unable to extend her winning run from qualifying despite mounting a second-set fightback against Krejcikova.

After losing six of the first eight games, Sharma eventually submitted in one hour 14 minutes.

Nick Kyrgios, who faces 18th seed Roberto Bautista-Agut, plays later on Tuesday.

AAP