The Serb closed out his trophy case with the Olympic title weeks ago in what he described as the biggest achievement of his career, beating young rival Carlos Alcaraz in the Paris finale.
But from that highest of highs came a crushing low in New York as Djokovic suffered his earliest exit from the year's final major since 2006. He will finish the season without a Grand Slam title for the first time since 2017.
"I spent a lot of energy winning the gold and I did arrive to New York just not feeling fresh," he said. "I didn't have any physical issues. I just felt out of gas, you know, and you could see that with the way I played."
There were signs of trouble almost immediately when he began his campaign for a record 25th major title. In a shaky win over qualifier Radu Albot in the first round, he him racked up nearly twice as many unforced errors as winners.
He struggled in the sweltering conditions during the second round before compatriot Laslo Djere gave him his 90th win at the US Open, retiring midway through the third set.
"From the first match, I just didn't find myself at all on this court. It's all I can say," Djokovic told reporters.
On Friday, he produced an astonishing 14 double faults and lost his way trying to slow down the fine performance by Popyrin, losing 6-4 6-4 2-6 6-4 a night after Alcaraz suffered a shock exit of his own in the second round.
"I tried so many things, and sometimes that's an issue, you know, is that you move away from the basics that work. Then you just lose the basics. You lose the foundation," he said.
"It was just really a big struggle mentally for me to play these three matches here, because I wasn't playing even close to my best."
It will be the first time since 2002 that none of tennis' "Big Three" - Djokovic, Rafa Nadal and the retired Roger Federer - have picked up a major in a season, the latest sign of a changing of the guard in the men's game.
"Sitting from a larger perspective, of course I have to be content," Djokovic said.
"It's hard to see the big perspective right now, you know. You're just angry and upset that you lost and the way you played and that's it."
--Reuters--