Nadal took five hours and 15 minutes to make history in Sunday's final - which went well into the early hours of Monday morning in Melbourne - as he recovered admirably to sink Medvedev.
The US Open champion came out all guns blazing as a very sweaty Nadal battled back from two break points in the first set, but Medvedev recovered from a 1-2 deficit to win the first set 6-2 as Nadal hit the net.
Nadal finally had two break points to his name in the second set after a 40-shot rally in the fourth game - Medvedev saved one with an ace before hitting long as the Spaniard went 3-1 up.
However, Medvedev soon displayed true grit and determination to fight back and force a tie-break following a brief interruption due to a court invader, as the Russian's passing shot saw him lead the match 2-0.
Nadal immediately missed an opportunity to break in the third set but did so in the ninth game as Medvedev acknowledged the riled-up crowd, with the Spaniard taking the set and forcing a fourth with a love hold.
With most of those in attendance at the Rod Laver Arena clearly rooting for Nadal, they enjoyed Medvedev's next double fault as Nadal broke for a 2-1 lead, with the 35-year-old ensuring that the final would go the distance with another love hold at 5-4.
Nadal earned the vital break in the deciding set to move 4-2 up and found himself serving for the 21st Grand Slam title a little while later, but a double fault and shots into the net allowed Medvedev to stay in the tie.
With the two tireless competitors unable to be separated at 5-5, Nadal broke Medvedev's serve once more and make it second time lucky with the ball in his hand, confidently serving for the championship and writing another chapter in the history books. body check tags ::