Thompson sent world No.7 Hubert Hurkacz packing with a spirited 7-6 (7-2) 6-1 7-5 victory to join fellow Sydneysider Alexei Popyrin in the last 32 at Flushing Meadows.
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 huge opportunity of a deep run.
The 30-year-old will play Italian Matteo Arnaldi next looking to equal his career-best grand slam charge to the fourth round in New York in 2020.
Arnaldi is ranked just two spots higher than Thompson at No.30 in the world.
Hurkacz, famous for ending Roger Federer's 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.
He broke back in the ninth game before claiming the opening set in a tiebreaker.
Thompson romped through the second set but the Pole fought back in the third.Â
Twice Thompson had to serve his way out of trouble from two break points down to keep Hurkacz at bay before holding his nerve to close out the match in straight sets after two hours and 23 minutes.
The seventh-seeded Hurkacz is the highest-ranked player to crash out of the men's event.
Five more Australians were scheduled for second-round action on day four, including 10th seed Alex de Minaur against Finnish qualifier Otto Virtanen.
Thanasi Kokkinakis, Chris O'Connell, Max Purcell and wildcard Tristan Schoolkate are also chasing spots in the last 32.
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