Chasing a record-extending 25th major title, Djokovic was playing his first tournament since winning the gold medal at the Paris Olympics.
But the Australian, who secured his maiden ATP Masters 1000 title in Montreal earlier this month, outmuscled 37-year-old Djokovic with a fearless brand of tennis to seal the biggest win of his career under the lights of Arthur Ashe Stadium.
Djokovic, who had to dig deep to win the Olympic gold medal against Alcaraz earlier this month, failed to convert five break point opportunities in the opening set, while Popyrin broke serve on his first chance for a 5-4 lead and then grabbed the first set.
Popyrin broke again when Djokovic’s forehand volley landed wide for a 3-2 advantage and he soon 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 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 3-2 lead in the fourth.
He completed the upset when Djokovic’s forehand sailed long on match point.
The last time Djokovic did not taste Grand Slam glory in a season was in 2017 as he suffered his earliest loss at Flushing Meadows since 2006.
