The Spaniard claimed his second title in Melbourne in a five hour, 24 minute thriller, rallying from a two-set deficit against the Russian as he broke the tie with Roger Federer and Novak Djokovic by claiming his 21st Grand Slam.
Nadal makes history, fights from huge deficit to triumph at year's first Slam
Medvedev started the stronger as an ace out wide gave him a dominant hold and he had a pair of break points on the Nadal serve, but the Spaniard's underrated net game got the job done.
From there the Russian stamped his authority on the first set, a pair of Nadal backhand errors handing him the break and a 3-2 lead.
A second break, which Medvedev won to love, gave him a commanding 5-2 advantage and he had little problem closing out the set as Nadal missed on another return.
The 2009 champion stopped the run of five games on the trot for Medvedev with an opening hold in the second set. The fourth game featured a mesmerizing 40-shot rally, capped with a sublime backhand slice winner by Nadal.
That shot gave him two break points and after converting the second of those chances, he snuck in front 3-1. The lead was eventually stretched to 5-3 after breaks were traded, the Spaniard serving for the set.
Showing why he is the best hard court player in the world at the moment, the second seed clawed back to force a tiebreaker.
Much like the set itself, the breaker saw Nadal take control, a volley wide by Medvedev putting the Spaniard in the ascendancy 3-2.
The Russian again overturned a_5-3 deficit, winning the final four points, closing with a glorious backhand winner down the line to assume a two-set lead.
After saving two break points and closing out the first game of the third set with consecutive aces, it appeared Medvedev was on cruise control despite Nadal finding his serve rhythm.
While the sixth seed's forehand was doing most of the damage, it was the backhand that eventually came through for him, firing off a glorious one to break for a 5-4 lead.
Unlike the second set when he couldn't close the deal when presented with the opportunity, Nadal made no mistake here, wrapping up the third with winners from both wings and the battle was well and truly on.
Medvedev called for the trainer in the beginning of the fourth set, though he looked to be alright when having two break points, unable to convert either opportunity.
The intensity rose with each passing shot and Nadal carved out a pair of break points, the first saved with an ace by the Russian, the second gift-wrapped with a double fault.
Armed with a 2-1 advantage, the lead was surrendered and then regained in a two-game span, the Spaniard was back on top, securing another break with a deft passing shot after luring Medvedev in.
The second seed was now laboring physically, a product of his previous two matches being long, drawn out affairs, although he did save a set point to force Nadal to serve it out.
With the momentum clearly on his side, another forehand winner brought up triple set point and Nadal needed only one chance, jamming Medvedev with a superb body serve to level the match.
The crowd could hardly believe what they were seeing as the living legend Nadal was a set away from history as both men looked for any opening they could get.
A stressful hold was followed by a comfortable one, Medvedev jumping in front 2-1. That would be his last lead on the evening as the Nadal forehand powered him to a break.
Sensing the end was near, the Spaniard swatted away three break points to make it 4-2 and he inched closer with another hold, a game from history as the match hit the five-hour mark.
Medvedev wouldn't go quietly, summoning whatever he had left in the tank to break to square the decider at 5-5 as another chapter in this tennis epic was being written.
Amazingly, at deuce, the Russian was helpless to watch another thundering forehand winner from Nadal and when his own backhand went wide, he faced break point, given when a tired-looking forehand missed.
With a second chance to grab the title, Nadal raced out to a 30-0 lead, an ace brought up triple championship point and he needed only one chance to put away the match, take his place in history and treat us to a sporting moment we surely will never forget.