Alex de Minaur and Jordan Thompson have risen to the occasion to help continue Australia's best start to a US Open in almost 30 years.

Thompson claimed the biggest scalp of the tournament yet, sending world No.7 Hubert Hurkacz packing with a rollicking 7-6 (7-2), 6-1, 7-5 victory to open day four at Flushing Meadows.

Backing up from his first match in seven weeks, de Minaur recovered from an early deficit to see off Finnish qualifier Otto Virtanen 7-5, 6-1, 7-6 (7-3) after Chris O'Connell also progressed with a 6-3, 6-4, 3-6, 6-3 win over Italian Mattia Bellucci.

With Alexei Popyrin already through and set to square off with defending champion Novak Djokovic at 9am Saturday (AEST), Australia have four men in the last 32 in New York for the first time since 1997.

De Minaur will be relieved about advancing to the third round for the sixth time in the past seven years.

The 10th seed conceded after his four-set tournament opener on Tuesday he was playing less than 100 per cent fit and without his usual movement having been sidelined since Wimbledon with a hip injury.

The 2020 Open quarter-finalist's prospects of another deep run didn't look flash when he fell behind 5-2 in the first set.

De Minaur, though, battled back to reel off seven straight games to take a stranglehold on the match.

His lower-ranked rival hung tough in the third, but so did de Minaur to prevail in a tiebreaker and book a third-round date with Dan Evans or Mariano Navone.

After missing a grand slam seeding for the first time by just one rankings spot, Thompson has taken matters into his own hands to give himself a golden opportunity to match his charge to the last 16 in 2020.

Hurkacz, famous for ending Roger Federer's storied Wimbledon career, appeared in control early, racing to a 5-2 lead in the first set.

That's when Thompson, proudly decked out in the Australian green and gold, stepped up.

Little wonder the 30-year-old was left elated to have been able to subdue the ATP's season ace leader and blow his section of the draw wide open.

The seventh-seeded Hurkacz is the highest-ranked player to crash out of the men's event.

"A good day at the office," Thompson said.

"Down early in the first, he served for the first set and he's got one of the best serves on tour.

"So to turn it around like I did was pretty impressive, even if I say so myself."

Thompson faces Italian world No.30 Matteo Arnaldi next and could meet de Minaur in the fourth round.

O'Connell earned a show-court crack at world No.1 Jannik Sinner with his victory over Italian Mattia Bellucci.

O'Connell, also 30 and from Sydney's northern beaches, backed up his first-round upset win over 26th seed Nicolas Jarry with an equally steely display.

He looked on course for a straight-sets romp before having to dig deep after losing the third set from a service break up.

O'Connell rebounded to take the 56-minute fourth set to seal his place in the last 32 of a grand slam for only a second time — and first outside of Australia.

As well as a shot at Australian Open champion Sinner, O'Connell is guaranteed the biggest pay day of his career with a cheque for at least $US215,000 ($A315,000) coming his way.

But Thanasi Kokkinakis suffered a disappointing let down to bow out.

Two days after eliminating dual grand slam finalist Stefanos Tsitsipas, Kokkinakis crashed to a deflating 6-4, 7-5, 7-5 second-round loss to Portuguese baseliner Nuno Borges.

Jordan Thompson def. Hubert Hurkacz 7-6 (7-2), 6-1, 7-5

Chris O'Connell def. Mattia Bellucci 6-3, 6-4, 3-6, 6-3

Nuno Borges def. Thanasi Kokkinakis 6-4, 7-5, 7-5

Alex de Minaur def. Otto Virtanen 7-5, 6-1, 7-6 (7-3)

Tommy Paul def. Max Purcell 7-5, 6-0, 1-0 (walkover)

Jakub Mensik def. Tristan Schoolkate 6-7 (4-7), 2-6, 6-2, 7-6 (7-5), 7-6 (10-3)