The legendary Serb fell at the earliest hurdle at the US Open for 18 years as he was beaten 6-4 6-4 2-6 6-4 by the 28th seed from Australia.
The 37-year-old claimed Olympic gold in Paris but he will end the year without a Grand Slam title for the first time since 2017.
Djokovic was not sugarcoating his performance, saying the âawfulâ display was as bad as he has played ever.
âI have played some of the worst tennis I have ever played,â he said. âHonestly, the way I felt and the way I played from the beginning of this tournament, third round is a success.
âIf you play on a quick surface like this without, you know, the serve, without ability to win free points there, very low first-serve percentage, many double faults, then you canât win.
âYou canât win, especially against the guys who are in form like Alexei who is serving big, puts a lot of pressure on your service game. Yeah, it was just an awful match for me.â
There was no injury concern for Djokovic, but admitted that he struggled for energy throughout the event.
âI tried my best, I didnât have any physical issues,â he said. âI just felt out of gas, and you could see that. From the first match, I just didnât find myself on this court.
âLife moves on. Iâll try to recalibrate and look forward to whatâs next. Congratulations to him and his team. He definitely played better and deserved to win today.â
It is another shock at Flushing Meadows after Carlos Alcaraz was beaten by Botic van de Zandschulp in the second round.
Jannik Sinner is now clear favourite to lift the trophy with the bookmakers, followed by Alexander Zverev and Daniil Medvedev.
For more stories like this, check our sport page.
Follow Metro Sport for the latest news on
Facebook, Twitter and Instagram.
MORE : British No.1 tennis star left hurt after suffering âhorrendousâ US Open defeat
MORE : US Open star throws up midway through match before battling to gruelling victory
MORE : US Open star in floods of tears during interview after ending opponentâs career