Dane Sweeny has won a real-life David-versus-Goliath battle to rock the US Open with a stunning second-round upset over dual grand slam semi-finalist Lorenzo Musetti.

The unheralded Australian wildcard took down the 14th seed 3-6, 6-1, 6-2, 6-2 on Friday morning (AEST) for the biggest win of his career.

Standing only 170cm high, Sweeny rose to the occasion to reach the third round of a grand slam for the first time and earn a minimum pay day of $US290,000 ($A402,750).

For a couple of heady hours it looked like his underdog countrymen Tristan Schoolkate and Alexei Popyrin would join Sweeny in round three.

But Schoolkate's inspired run from qualifying finally came to a halt at the hands of fifth-seeded French Open runner-up Flavio Cobilli.

Schoolkate snatched the first set before the Italian showed his class to prevail 3-6, 6-3, 6-4, 7-5 after two hours and 41 minutes in New York's scorching summer heat.

And two years after upstaging Novak Djokovic in the US Open's third round, Popyrin fell short of a place in the last 32 once again, losing a tense four-set battle with Chilean Alejandro Tabilo.

Like Schoolkate, Popyrin took the opening set before the 25th-seeded South American claimed two pivotal tiebreakers, then the match 2-6, 7-6 (7-4), 7-6 (7-3), 6-2 to seal a likely third-round date with German top seed Alexander Zverev.

But ranked more than 100 places below his world number 14 opponent, Sweeny is savouring a mighty breakthrough after bossing Musetti into submission.

He ran the 14th seed ragged and had the Italian looking in particular distress when he required a medical time-out after falling behind a double break at 0-3 in the all-important third set.

Even after clawing one break back, Musetti — who has made the Wimbledon and French Open semi-finals over the past two years — continued remonstrating animatedly to his courtside box.

Despite sporting a massive ice pack on his right elbow after his first-round win, Sweeny continued diving like Boris Becker for acrobatic winning volleys at the net.

And the 25-year-old was duly rewarded with a last-32 shot at another Italian, world number 22 Luciano Darderi on Saturday (AEST) — and a rankings rise to a career-best 115 in the world, or better.

"I'm just grateful to be even able to compete in grand slams. The tennis journey is such a rollercoaster," Sweeny said.

"And to soak up the atmosphere and get a win, a couple of wins, in front of this crowd, is awesome."

AAP