The Russian had hoped it would be third time lucky on Rod Laver Arena on Sunday, having lost the 2021 and 2022 finals at Melbourne Park to Novak Djokovic and Rafa Nadal.
The third seed took the first two sets with some brilliantly aggressive tennis only for the Italian to rally for a 3-6, 3-6, 6-4, 6-4, 6-3 victory and claim his first Grand Slam title.
"It's very, very tough when you have a mentality, I don't want to say champion, but a good mentality, a sport mentality, it's very tough to lose in the final," he said.
"It kind of hurts more maybe than to lose in semis or quarters. But you have to try to find positives, and the positive is, well, the final is better than the semi-final and quarters."
The 2021 US Open champion has now lost five of the six Grand Slam finals he has played, three of them after leading by two sets.
The other two five-set losses came at the hands of Nadal, the Spaniard rallying to claim the 2019 U.S. Open title and the Australian Open title two years ago.
Medvedev made very dark comments about the death of his dreams after the 2022 final and said his more philosophical attitude this year was a reflection of a change in his outlook towards tennis and life.
"I am different. I am different," he said. "I managed to ... become a different person with different mentality.
"I'm really going to try to make everything possible with myself, with my mind, for this loss to not affect my future tournaments and future seasons."
Medvedev had already spent more than 20 hours on court before the final thanks to his five-set wins over Emil Ruusuvuori in the second round, Hubert Hurkacz in the quarter-finals and Alexander Zverev in the semis.
It was perhaps then no surprise that he would tire in the fifth set of Sunday's three-hour, 44-minute final but unfortunately for him, Sinner, who had played four hours fewer, did not.
"I was fighting, I was running. I was, like, 'I will try, if tomorrow I don't feel my legs it doesn't matter, I'm going to try everything I can today until the last point', and I did," Medvedev said.
"He didn't seem as tired as my opponents before. He started playing better. I got a little bit tired. Serve went a little bit worse. So the momentum changed and I really tried in my mind to change it back again.
"But I didn't manage to do it, and that's why he's the winner and has the trophy."
