The deciding fourth set was a memorable one, with the pair trading outrageous winners along with untimely errors, the most costly of which was a double fault from 11th seed Tsitsipas on break point in the ninth game.
The 20-year-old Michelsen then served out the match 7-5 6-3 2-6 6-4 on Monday to claim the biggest win of his burgeoning career.
"First of all I just tried to stay super composed out there," said Michelsen, who struggled at times with his second serve in the deciding set.
"I knew it was going to be a battle out there to the end."
Michelsen paid tribute to his mother Sondra, a former college player who has been his biggest supporter since he took up the sport aged three.
"We'd hit a million balls from the baseline every day," he said.
"We'd go like 30 minutes up the middle, then we go across each way for an hour and a half.
"There's no chance I'd be here without without her, so thanks Mum. Love you."
It was the first time since 2018 that Tsitsipas had lost in the first round at Melbourne Park.
Stefanos Tsitsipas came up short against rising US star Alex Michelsen at the Australian Open. (James Ross/AAP PHOTOS)
He lost the 2023 final to Novak Djokovic and had also reached the semi-finals at Melbourne Park on three other occasions.
But the prospect of securing that elusive maiden major title must seem further away than ever, with Tsitsipas admitting he no longer had the same desperate hunger to succeed.
It's a far cry from the heady days of 2019, when he beat the great Roger Federer at Melbourne Park and seemed well on the way to being the sport's next big thing.
"For sure I had a fresher mind back then," Tsitsipas said.
"It seemed like I was hungrier in a completely different way than I am now."
Michelsen's second-round opponent will be Australian wildcard James McCabe, who trounced Spanish qualifier Martin Landaluce 6-4 6-3 6-4.
American No.17 seed Frances Tiafoe was made to work hard by Frenchman Arthur Rinderknech before advancing 7-6 (7-2) 6-3 4-6 6-7 (4-7) 6-3.
World No.1 Jannik Sinner starts his title defence against Chilean Nicolas Jarry.
The two feature matches of Monday's night session involve 24-time major winner Novak Djokovic and No.3 seed Carlos Alcaraz.
