"I'm speechless. I have no words to describe what just happened on the court. My tennis speaks for itself," Tsitsipas said after the match.
Second-seeded Nadal took the first two sets fairly easily to run his streak of consecutive sets won at major tournaments to 35.
But Nadal made some mistakes in a third-set tiebreaker and dropped it.
Tsitsipas then took the fourth set, too.