The match was billed as the hottest ticket in New York and lived up to the hype, with a scoreline that belied its intensity, as the 2022 champion Alcaraz soaked in deafening cheers on match point.
Djokovic had won their two most recent meetings, including in the quarter-finals of the Australian Open earlier this year, but the 38-year-old showed wear-and-tear against the Spaniard 16 years his junior.
"I'm happy with my level of tennis, but you know, it's just the physicality of it," said Djokovic, who lifted the last of his four U.S. Open titles two years ago.
"It will be very difficult for me in the future to overcome the hurdle of Sinner, Alcaraz, in the best-of-five on the Grand Slams. I think I have a better chance (in) best-of-three, but best-of-five, it's tough."
The seventh seed's showdown with the Spaniard 16 years his junior on Friday was billed as the hottest ticket in New York, where a rapt, celebrity-packed Arthur Ashe Stadium urged on the Serb two decades after his Flushing Meadows main draw debut.
He put up a reasonably clean performance, pulling out a few nifty tricks at the net with his trademark creativity, but could not match his opponent's intensity, producing roughly half as many winners as Alcaraz.
"I'm not giving up on Grand Slams," said Djokovic, who lost to Sinner in the Wimbledon and Roland Garros semis after retiring in his semi-final clash with Alexander Zverev in the Australian Open this year.
"I'm going to continue fighting and trying to get to the finals and fight for another trophy at least. But, you know, it's going to be a very difficult task."
His next stop on the ATP Tour will be in Athens, and Djokovic said it was too soon to say whether he would play at Melbourne Park next year.
"At least at this stage of my career, I mean, I'm not thinking that far," he told reporters. "I still want to play Grand Slams, Grand Slam season, full Grand Slam season next year. Let's see whether that's going to happen or not."