The 35-year-old Spaniard has broken the men's record for most Grand Slam singles titles.
He was broken when serving for the championship at 5-4 in the fifth set but made no mistake the next time.
It was the second-longest Australian Open final after Novak Djokovic beat Nadal in five sets in 5 hours and 53 minutes in 2012.
Nadal now has one more than Roger Federer and Djokovic, his long-time rivals in the so-called Big Three.
The 35-year-old, who clinched the trophy in Melbourne in 2009, has also become just the second player in the Open Era alongside Djokovic to win each of the four majors at least twice.
Nadal now leads Medvedev 4-1 in their ATP Head2Head series
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