The 22-year-old Greek inflicted only the second defeat on the great Spaniard in which he has lost after winning the first two sets.
Tsitsipas won 2-6, 3-6, 7-6, 6-4, 7-5 in just over four hours before an empty Rod Laver Arena to make the semi-finals, in which he will face Russian Daniil Medvedev.
Stefanos Tsitsipas came from two sets down to stun Rafael Nadal in the Australian Open
The world No 2 was beaten 2-6 3-6 7-6 6-4 7-5 in a thriller that lasted over four hours
‘I’m speechless,’ said Tsitsipas afterwards. ‘I focused to staying calm and holding my nerves. I have no words to describe what just happened.
‘It’s an unbelievable feeling to be able to fight at such a level and leave it all on the court. I started very nervous and I don’t know what happened after the third set. Everything was working for me. The emotions are indescribable.’
There were shades of 2019, when Tsitsipas recovered from losing the first set to shock Roger Federer in four sets.
Tsitsipas described the emotions of stunning major challenger Nadal as ‘indescribable’
Nadal made a series of errors in the fifth set which ended up costing him the quarter-final
Nadal overcame a hesitant start to gain near total control until midway through the third set, and still looked on course until the tiebreak, which he partly tossed away with a series of shanks and miscued overheads.
Having gained the lifeline, the young Greek went into overdrive, with his previously misfiring forehand becoming more and more efficient.
Surprisingly, the physicality of Tsitsipas proved stronger than that of the French Open champion, who will for now not overtake Roger Federer’s 20 Grand Slam titles.
Nadal was in total control until he let his lead slip and his Greek opponent took advantage
At 5-5 in the fifth set Nadal was broken with a slew of errors. When it came to serving it out he threatened to come back by defying two match points, before the Greek finally nailed it with one last flowing backhand down the line.
A breathtaking contest ended with Tsitsipas winning 145 points to 142 for Nadal in what looked like a coming of age performance.