Djokovic had five break-point chances in the opening set but failed to convert any of them, while Popyrin broke serve on his first opportunity for a 5-4 lead before grabbing the first set.
Popyrin broke again in the second when Djokovic’s forehand volley landed wide for a 3-2 advantage. He took control of the match with a perfectly executed serve and volley to capture the second set.
The second-seeded Djokovic showed some life in the third when he broke serve with a forehand that Popyrin could not handle and took the set to claw his way back into the match.
But the comeback proved short-lived, with Popyrin letting out a mighty roar when he crushed a ferocious forehand winner for a break of serve and a 3-2 lead in the fourth. He completed the upset when Djokovic’s forehand sailed long on match point.
Djokovic was uncharacteristically sloppy in the contest, issuing 14 double faults, a record for him in a Grand Slam match.
The upset on Arthur Ashe Stadium came one night after third seed and tournament favourite Carlos Alcaraz, who finished runner-up to Djokovic at the Paris Games, was stunned in straight sets by unseeded Dutchman Botic van de Zandschulp.
Next up for Popyrin is a fourth-round meeting with American Frances Tiafoe.