Australia’s 28th seed Popyrin stood with his arms aloft as he wrapped up a surprise 6-4 6-4 2-6 6-4 win to hand Djokovic his earliest US Open exit in 18 years.
The Serb will end the year without winning a Grand Slam for the first time since 2017, while his search for a record 25th major title goes on.
Djokovic was far from his clinical best, serving a career-high 14 double faults in a Grand Slam match and committing 49 unforced errors.
“I have played some of the worst tennis I have ever played,” the 37-year-old said.
“Honestly, the way I felt and the way I played from the beginning of this tournament, third round is a success.”
Djokovic’s exit follows that of French Open and Wimbledon winner Alcaraz, who lost to unseeded Dutchman Botic van de Zandschulp in the second round.
He said he “spent a lot of energy” winning Olympic gold – his self-proclaimed “biggest sporting achievement” – earlier this month.
“I tried my best, I didn’t have any physical issues. I just felt out of gas, and you could see that. From the first match, I just didn’t find myself on this court.” Djokovic added.
“Life moves on. I’ll try to recalibrate and look forward to what’s next.”
Popyrin, 25, will make his first fourth-round appearance at a Grand Slam when he faces Frances Tiafoe, who moved past fellow American Ben Shelton in a five-set thriller.
