The 25-year-old Russian defeated Djokovic 6-4 6-4 6-4 in two hours and 15 minutes, sending down 16-6 aces, along with 38-27 winners.
The triumph is Medvedev’s first major victory, having lost to the Serbian in the Australian Open final earlier this year.
It also ends Djokovic’s dreams of winning all four slams in the same calendar year, having also had his golden slam hopes dashed after losing to Alexander Zverev in the Tokyo Olympics semi-finals.
“Amazing, amazing match,” Djokovic said during the post-match presentation. “If there is anyone that deserves a grand slam title right now, it is you.
“I wish you many more grand slams and many more majors to follow.”
Medvedev’s triumph comes at his third attempt in a major final, having lost to Rafael Nadal in the 2019 US Open decider.
“Today maybe you were a little bit more for Novak, but that’s completely understandable,” Medvedev said about the Arthur Ashe Stadium crowd.
“Throughout the week you gave me a lot of energy, starting from 2019, long ago. It helped me ‘til today. It was not easy, but thanks a lot.”
The Russian was gushing in praise for 34-year-old Djokovic, who remains level with 20 majors alongside Nadal and Roger Federer.
“First of all I want to say sorry for you fans and Novak. We all know what he was going for today,” Medvedev said.
“I’ve never said this anybody, but I will say it right now, for me you are the greatest tennis player in history.”