The world number six clawed his way back to a gruelling victory after having dropped the first two sets against the world number two Medvedev in Melbourne.
He won the epic encounter 2-6, 6-7 (5), 6-4, 6-4, 7-5 in five hours and 24 minutes on Sunday.
The win edged Nadal to a record 21 major wins, ahead of his closest rivals Novak Djokovic and Roger Federer.
Nadal had come into the tournament after catching COVID-19 last month and nursing a foot injury that had sidelined him for four months last season.
“One month and a half ago, I didn’t know if I will be able to be back on the tour playing tennis again and today, I’m here in front of all of you having this trophy with me,” said Nadal after the match.
“You really don’t know how much I fought to be here,” he added.
Medvedev was chasing history himself on Sunday, aiming to become the first man in the Open era to win his second Grand Slam title at the very next major following his U.S. Open title last year.
He defeated Djokovic in that final in New York in September.
Despite coming close and failing to capture his second Grand Slam title, Medvedev was gracious in defeat, praising Nadal for his standard of play.
“I want to congratulate Rafa because what he did today, I was amazed,” he said.
“It was insane. I think the level was very high ….You are an amazing champion.”
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