The Italian fourth seed was blown off course in the first two sets but recovered to win 3-6, 3-6, 6-4, 6-4, 6-3 in three hours and 44 minutes.
The result is a bitter blow for the Russian third seed, who has now lost a second Australian Open final after being two sets up, following his defeat by Rafael Nadal in 2022.
Medvedev came into the match boasting a 6-3 winning record against the 22-year-old but had lost the past three matches.
The Russian had played three grueling five-setters at Melbourne Park and spent nearly six hours longer on the court than Sinner before the final.
But, looking fresh, he was quickly into his stride, unsettling the usually calm Sinner, who could not find any rhythm.
The Italian, playing in his first Grand Slam final, was broken just twice in the entire tournament in the run-up to Sunday’s title decider but Medvedev doubled that tally in the first set.
World number four Sinner was again in deep trouble at the start of the second set, fending off multiple break points against a hungry Medvedev and pleading for backing from the crowd on Rod Laver Arena.
He survived that onslaught but was broken for a third time in the match in the fourth game when a poor drop shot allowed the Russian to set up a winner.
Medvedev Raced Through his Service Game to Love
Medvedev raced through his service game to love, giving Sinner no time to gather his thoughts.
He hit a fierce forehand to set up two more break points in the sixth game and Sinner went wide with a forehand to slip 5-1 down.
The Italian broke back immediately and had another break point in the ninth game to put the set back on serve but Medvedev snuffed out the mini-revival.
The third set was tighter and went with serve until the decisive 10th game.
Sinner put a forehand passing shot wide at the end of a 31-shot rally, missing out on the chance to earn two set points, but his chance came again and this time he took it to seal the set.
The momentum was now with Sinner and Medvedev, who required strapping for his foot, had to fight hard to hold early in the fourth set.
Sinner fired three aces to edge 4-3 ahead and broke in the 10th game when Medvedev fired long to take the match into a fifth set.
With the tension mounting, both players stayed solid on serve until the sixth game, when Medvedev dumped a backhand into the net to give Sinner three break points.
A forehand crosscourt winner gave the Italian a crucial break and he went on to take his first championship point.