Sinner became only the second player in the Open Era to win after trailing by two sets at the Australian Open, prevailing 3-6 3-6 6-4 6-4 6-3 in three hours and 46 minutes.
Medvedev also lost the 2022 decider to Rafael Nadal after leading by two sets in a cruel twist for the third seed Russian.
The fourth-ranked Sinner beat five seeds on his way to his maiden Slam crown, including 10-time Australian Open winner Novak Djokovic in the semi-finals.
Sinner only began playing on the ITF Circuit in 2018, winning his first ATP Challenger title in 2019. In 2022, he was reached the quarter-finals at both the Australian Open and the US Open.
The 22-year-old made his maiden major semi-final in 2023 when he reached the final four at Wimbledon but lost to Djokovic in straight sets.
But since then Sinner has become one of the form players on the ATP circuit, beating Djokovic at the ATP Finals, along with the Australian Open semi triumph.
On Sunday in Melbourne, Sinner delivered 14 aces and 50 winners, doing well to win 54% of second serve points and saving 8 of 12 break points.
“It is the happiest land (Australia), it is a very nice place to be, in Europe there is snow and where my parents are it is -20 degrees in the morning, so it is better running in the sun here,” Sinner said.
“I want to thank everyone for making this land so special.”