Medvedev defeated the Serbian 6-4 6-4 6-4.
Novak was on the verge of winning a complete title victory this year as he had already clinched Australian Open, French Open and Wimbledon titles.
The iconic Serbian was chasing a record 21st Grand Slam men's title this time.
“It definitely makes it sweeter,” he told US Open website. “For the confidence and for my future career, knowing that I beat somebody who was 27-0 in a year in Grand Slams, I lost to him in Australia, he was going for huge history, and knowing that I managed to stop him it definitely makes it sweeter and brings me confidence for what is to come.”