Popyrin defied searing heat in New York to grind down Spaniard Pedro Martinez 6-2 6-4 6-0 as a trio of his Australian cohorts crashed back to earth on day three.
The men's 28th seed was made to work hard in the heatwave conditions, twice having to fight back from a service break down in the second set.
Popyrin, though, showed his mettle to pull through in one hour and 48 minutes, Â his supreme final set sending a statement to Djokovic.
"It was really hot. Probably after the Olympics this year, this is probably one of the hottest conditions I've played in," Popyrin said.
"At moments, I felt quite rough but I trusted my fitness. I trusted my team and the most important thing, especially in this weather, was that we got through in straight sets and we have the maximum time to recover now.
"That was my biggest focus throughout the match."
Alexei Popyrin (left) will meet Novak Djokovic (right) at a grand slam for the third time this year. (James Ross/AAP PHOTOS)
Chasing an unprecedented 25th grand slam singles crown, second-seeded Djokovic advanced when his Serbian countryman Laslo Djere retired with an apparent abdominal muscle strain while 6-4 6-4 2-0 in the men's feature night match.
Popyrin has yet to drop a set en route to the last 32 and blasted another 13 aces on Wednesday (Thursday AEST) in the perfect tune-up for Djokovic.
The freshly crowned Montreal Masters champion has recent experience against the super Serb, having lost in four sets twice this year already at the Australian Open and Wimbledon.
"I had chances in both matches and it's just a matter of taking those chances and playing good on the big points. That's what he did," Popyrin said.
Meanwhile, Popyrin's compatriot Rinky Hijikata was earlier dealt a grand slam reality check.
Hijikata was no match for Grigor Dimitrov, suffering a 6-1 6-1 7-6 (7-4) thrashing at the hands of the Bulgarian ninth seed to bow out in the second round.
Former women's quarter-finalist Ajla Tomljanovic and 18-year-old qualifier Maya Joint were also eliminated on day three at Flushing Meadows.
With 10 players making the second round, Australia's bumper 20-strong contingent had made their brightest start to the Open in 45 years.
The men, in particular, have been on fire, with eight Australians winning their opening matches for the first time since 1976 - almost half a century ago.
Hijikata stormed to the fourth round last year as a wildcard but knew he'd have his work cut out against Dimitrov, who is playing his best tennis at age 33.
Hijikata, though, could not have imagined winning only two games in the first two sets.
The 23-year-old put up more of a fight in the third, but the one-time world No.3's class ultimately prevailed as Dimitrov won through in two hours and 10 minutes.
Madison Keys shakes hands with Maya Joint (left) after their second-round match. (AP PHOTO)
Tomljanovic lost her second-round match 6-3 6-2 to Belgian 33rd seed Elise Mertens, while Joint's breakout grand slam run came to a halt with a 6-4 6-0 loss to 2017 runner-up Madison Keys.
Despite the defeat, Joint is projected to leave New York with a career-high ranking of No.108 in the world and on track to gain direct entry to the Australian Open in January, after winning three qualifying matches then posting her posting maiden main-draw grand slam victory.
12°C