The world number one triumphed 6-7 (6/8), 2-6, 6-3, 6-2, 6-4 over the Greek 22-year-old who was playing in his first Slam final.
Browsing: Novak Djokovic
The two warriors produced superhuman tennis as the 58th duel between them arguably rivalled anything they had conjured against each other since they first locked horns in 2006.
The world number one looked out of sorts before rallying, leading 6-7 (7-9) 6-7 (2-7) 6-1 6-0 4-0 when the Italian retired with an injury.
The Spaniard recovered from a potentially dangerous fall after tripping over a raised line to take the latest installment of the most-played rivalry in modern men’s tennis.
The final in Rome is the 57th time they play against each other in history; their last encounter was at the 2020 French Open final, where the Spaniard won in straight sets.
Rival Novak Djokovic had already sealed his progress earlier in the day, beating Alejandro Davidovich Fokina in dominant fashion, but Nadal found life hard against Denis Shapovalov.
The world number one took just an hour and 10 minutes to wrap up an emphatic 6-2 6-1 victory at the Foro Italico.
Federer, 39, is making his comeback after two knee operations and has not played a Grand Slam since January 2020.
Djokovic produced a clinical 6-4 6-2 win over up-and-coming Jannik Sinner on Wednesday before Nadal, the 11-time champion at the Country Club, thrashed Federico Delbonis 6-1 6-2.
The World no. 7 is the highest-ranked player who has withdrawn from Miami so far, joining Roger Federer, Rafael Nadal, Dominic Thiem and Novak Djokovic on the list of the most notable missing players.
Djokovic, who won his 18th major at the Australian Open in February, has now held the top spot for 311 weeks over the course of his career, beating Federer’s previous record of 310.
His latest triumph in Melbourne has brought the 33-year-old world number one Djokovic to within two of the record mark of 20 major wins shared by Roger Federer and Rafael Nadal.
The Russian was in outrageously good form yet again as he ruthlessly disposed of Tsitsipas in what was an utterly sublime display on Rod Laver Arena.
The world number one, who has won the title on each of the eight previous occasions he has reached the semi-finals in Melbourne, claimed his first straight-sets win since the first round, beating the world number 114 6-3 6-4 6-2.
Both advanced into the fourth round of the competition in five-set thrillers.
The players did something different by soaking up their freedom after 14 days of quarantine ahead of the Australian Open.
The development followed a threat of legal action from apartment owners at a luxury hotel in Melbourne
The 39-year-old Swiss, who has won the tournament six times, is recovering from the knee injury that has kept him out of action since losing to Novak Djokovic in the semi-final at the 2020 event.
Tournament Director Craig Tiley also assured that the safety of players and their staff is top priority, vowing a “happy slam” amid the coronavirus pandemic.
The Austrian third seed’s 7-5, 6-7 (10/12), 7-6 (7/5) win ended Djokovic’s hopes of equalling Roger Federer’s record of six titles at the elite eight-man event.