Popyrin, the newly-crowned Montreal Masters champion and 28th seed, is on course to meet Serbia's Olympic gold medallist in the third round in what would be their third grand slam meeting this season.
Djokovic won their previous two early-rounds encounters at the Australian Open and Wimbledon in four sets, but 28-year-old Popyrin did give the 24-time major champ an examination in both and will feel buoyed by his recent maiden Masters 1000 triumph in Canada.
Alex de Minaur is hoping to bounce back from his Wimbledon injury disappointment. (AP PHOTO)
First, though, Popyrin will have to find a way past South Korea's tricky Soonwoo Kwon in the opening round, before facing a potential second-round contest against Spain's Pedro Martinez or a qualifier.
Djokovic will also be up against a qualifier in his opener as he seeks the elusive 25th slam which would take him past the all-time mark he currently shares with Margaret Court.
Meanwhile, Australia's top hope Alex de Minaur, the 10th seed back in grand slam action after a hip injury prevented him playing Djokovic in the Wimbledon quarter-final, will open up against seasoned American Marcos Giron, with a qualifier awaiting in the second round.
But danger abounds as he's in the same quarter as No.3 seed Carlos Alcaraz, who is scheduled to meet Djokovic in the final as he did in his Wimbledon triumph and in the Serb's Olympic revenge mission.
With 10 Australian men's players inside the world's top 100 for the final slam of the year, which starts on Monday, there was perhaps an inevitability two would be drawn against each other.
This time, it's Max Purcell versus Aleksandar Vukic.
There were also tough opening draws for Thanasi Kokkinakis, up against 11th seed Stefanos Tsitsipas, Chris O'Connell, who faces Chilean 26th seed Nicolas Jarry, and resurgent James Duckworth, pitted against Italian 31st seed Flavio Cobolli.
Taylah Preston has drawn a former French Open finalist in the first round. (Darren England/AAP PHOTOS)
In the women's draw, Australian No.1 Daria Saville could face world No.1 Iga Swiatek in the second round if both get past qualifiers.
Teenage wildcard Taylah Preston will find grand slam life tough first up against former French Open finalist, 33-year-old Anastasia Pavlyuchenkova, the 25th seed.
The Australian men in the main draw were joined by a 12th on Thursday as Adelaide's Li Tu won through the final round of qualifying in three sets against Dutchman Jesper De Jong. The overseas grand slam debutant has yet to learn his first-round opponent.
The domestic women's contingent too was also expected to be bolstered with six Aussies in final-round qualifying action.
WHO THE AUSTRALIANS FACE IN THE US OPEN FIRST ROUND (PREFIX DENOTES SEEDING):
Men's singles
10-Alex de Minaur v Marcos Giron (USA)
Jordan Thompson v Constant Lestienne (FRA)
Chris O'Connell v 26-Nicolas Jarry (CHI)
Rinky Hijikata v Alejandro Davidovich Fokina (ESP)
Aleksandar Vukic v Max Purcell
28-Alexei Popyrin v Soonwoo Kwon (KOR)
Adam Walton v Alexandre Muller (FRA)
James Duckworth v 31-Flavio Cobolli (ITA)
Tristan Schoolkate v Taro Daniel (JPN)
Thanasi Kokkinakis v 11-Stefanos Tsitsipas (GRE)
Women's singles
Daria Saville v Qualifier
Ajla Tomljanovic v Qualifier
Taylah Preston v 25-Anastasia Pavlyuchenkova (RUS)
