His best result at a major came at last year’s US Open when he advanced to the fourth round. No.8 seed Roberto Bautista Agut looms as De Minaur’s likely obstacle to booking a quarter-final spot should he overcome Khachanov.
Christopher O’Connell and John Millman had the chance to continue an impressive campaign for the Australian men but were unable to deliver.
Millman came to the end of his campaign with a five-set loss to Frances Tiafoe.
Tiafoe took the first set in a tie-breaker but took his foot off the pedal before surging back to a 7-6 (8-6), 3-6, 3-1, 6-3, 6-3 win, setting up a clash with Marton Fucsovics, who beat 14th seed Grigor Dimitrov in five sets.
O’Connell had his work cut out against third seed Daniil Medvedev and showed some fight in the third but ultimately fell in straight sets 6-3, 6-2, 6-4.
Bautista Agut, meanwhile, got through a difficult second-round match against Serbian youngster Miomir Kecmanovic with a 6-3, 3-6, 6-3, 6-4 victory.
The Spaniard squandered 14 break-point opportunities but held his nerve in crucial moments to seal victory in just over two-and-a-half hours.
Kecmanovic, making his second consecutive second-round appearance at Flushing Meadows, stepped up the pressure on Agut’s serve in the second set to force an unlikely break at 5-3 and he went on to level the match.
Bautista Agut looked largely untroubled over the next two sets, however, as he patiently carved out two breaks of serve to book a place in the US Open third round for the first time in three years.
World No.11 Bautista Agut has now won five of his six matches since the tour’s resumption after the COVID-19 shutdown, reaching the semi-finals at the Western and Southern Open last week where he pushed eventual champion Novak Djokovic to a final-set tiebreak.
He will next face the winner of the all-Canadian clash between Milos Raonic and Vasek Pospisil.
Second seed Dominic Thiem did it easy against Sumit Nagal, beating the first Indian man to win a singles match at the US Open in seven years 6-3, 6-3, 6-2.
Things were less predictable in the women’s draw, however, with top 10 seeds Garbine Muguruza and Johanna Konta both eliminated.
Brit Konta won her first set against Romania’s Sorana Cirstea before losing the second in a tie-breaker to eventually fall 2-6, 7-6 (7-5), 6-4. Two-time major winner Muguruza was bounced out by Tsvetana Pironkova, who continues to enjoy her comeback after three years away from the sport.
The Bulgarian former Wimbledon semi-finalist showed little sign of rust after her break, during which she gave birth to her son Alexander.
“I always followed the news around the tour obviously, especially the Grand Slams. I always watched those,” said Pironkova, who reached the fourth round at Flushing Meadows in 2012. “But I really took some time off away from tennis in all aspects.”
“Little by little I started really missing the tour, started watching more tournaments, started to follow the players. I kind of started to make plans in my head looking at the calendar, which tournament would suit me best.”
Australian Open champion Sofia Kenin, meanwhile, put her lacklustre tune-up behind her with a 6-4, 6-3 win over Canada’s Leylah Fernandez.
Tunisian 27th seed Ons Jabeur now awaits the American, who lost in straight sets in her only warm-up event following the five-month COVID-19 shutdown.
Serena Williams’ bid for a record-tying 24th major continued with a routine 6-2, 6-4 win over Margarita Gasparyan of Russia.