Tsitsipas dropped the first two sets but stormed back to defeat Rafael Nadal, 3-6, 2-6, 7-6 (4), 6-4, 7-5.
Rafael Nadal's bid for a men's-record 21st Grand Slam title has ended with a five-set loss to Stefanos Tsitsipas in the Australian Open quarterfinals.
Tsitsipas dropped the first two sets but stormed back to defeat the No. 2-ranked Nadal, 3-6, 2-6, 7-6 (4), 6-4, 7-5, in a four-hour battle.
Nadal cruised through the first three sets and did not allow a break of his serve or even a break point, appearing as if he would keep control of the match. However, things took a turn in a surprisingly poor tiebreaker when he missed two overheads and hit a framed backhand to give the third set to Tsitsipas.
Tsitsipas mounted his epic comeback and took the fourth set. The 22-year-old appeared to gain more energy as the match went on while forcing a fatigued Nadal into more errors. Tsitsipas moved out front at 6-5 in the fifth by breaking at love as Nadal flubbed a series of shots, then served out the victory by converting his third match point with a backhand winner.
The only other occasion in which Nadal went from a two-set edge to a defeat in a Slam came at the 2015 U.S. Open against Fabio Fognini (who lost to Nadal in the fourth round at Melbourne Park this year).
"I have no words to describe what has just happened on the court, my tennis speaks for itself," Tsitsipas said in his on-court interview after the win. "It's an unbelievable feeling to fight at such a high level and leave it out on the court. I started very nervously. I don't know what happened after the third set. I flew like a bird and everything worked for me."
Nadal was attempting to continue his pursuit of Roger Federer, with who he is tied at 20 Grand Slam singles titles.
Instead, Tsitsipas will meet 2019 U.S. Open runner-up Daniil Medvedev in the semifinals on Friday. Neither Tsitsipas nor Medvedev has won a Grand Slam tournament.
The Associated Press contributed to this report.