The Greek, runner-up in Melbourne in 2023, lost 7-5 6-3 2-6 6-4 to American Alex Michelsen on the second day’s play.
The 11th seed had been due to play doubles with his brother, Petros, but withdrew before the tournament began to protect his singles chances.
“It’s quite ironic. My whole [idea] was to try to go deep. I knew the first thing I had to consider was not playing doubles,” Tsitsipas, 26, said.
“The whole purpose was just to save up on some energy and be fresher hopefully in the deeper draw of the tournament.
“I guess karma hit me. I was not able to deliver or play the way I was hoping to at this year’s event.”
Tsitsipas has long-been tipped as a future Grand Slam champion, having reached the Melbourne showpiece two years ago and the French Open final in 2021, losing both to Novak Djokovic.
However, he lost in the first round at last year’s US Open and in the second round at Wimbledon.
“The most frustrating part about losing in the first round of a Grand Slam is that you have way too much time to recover,” Tsitsipas added.
“It just sucks that I’ll be hanging around for quite a while now before my next tournament comes in.”
Elsewhere at Melbourne Park, world number one Jannik Sinner opened up his title defence with a 7-6 (7-2) 7-6 (7-5) 6-1 victory over Chile’s Nicolas Jarry.
Novak Djokovic begins his bid for a standalone record 25th Grand Slam singles title later on Monday, with Nick Kyrgios also making his return to tennis.
