In tough conditions on court 12 as the hot weather finally hit New York, Popyrin was trailing 6-2, 4-2 before he turned his game around.
Not only is the emerging Australian with a big serve yet to lose in the first round of a major, Popyrin has matched his effort of advancing to the third round at this year’s Australian Open, prevailing 2-6, 7-5, 6-3, 6-2.
The next match for Popyrin is a step up as he clashes with Matteo Berrettini after the Italian eliminated Australia’s Jordan Thompson.
While Popyrin and de Minaur won well, compatriot Thompson was a beaten in draining three-hour four-set match against the 24th seed, going down 7-5, 7-6 (7-5), 4-6, 6-2.
De Minaur will have to draw on his experience at Flushing Meadows from last year, when he pushed 2014 champion Marin Cilic all the way, racing to a two-sets-to-love lead before losing in five.
“I just went out there and took it to him and obviously it was a little bit of a heartbreaker but ultimately that is the way I have to play and that is what you want. You want to be playing these top guys at the top of their level,” de Minaur said.
“Hopefully I can really come out tomorrow and give it my best crack.”
De Minaur spent two hours and 21 minutes on court in dispatching Garin as the summer sun hit after persistent rain on Wednesday wiped out most of the day-three schedule.
With Nick Kyrgios and Thanasi Kokkinakis also aiming to join de Minaur and Popyrin in the round of 32 on day four, the youngster got the job done in style, winning 6-3, 7-5, 6-3.
De Minaur went close to racing through the final set after breaking the Chilean twice to race to a 4-0 lead but he dropped a game when serving for the match at 5-2.
The Australian has now reached the third round of a major four times.