The Russian, who has over 20 singles titles, was a runner-up at the 2019 US Open, when he lost out to Rafael Nadal.
During the nervy final moments of the clash, Medvedev was serving for the championship point in the ninth game in the third set, when things started to go south for the 25-year-old as the crowd wouldn't stop the jeers and boos while he served.
Although he initially struggled to hit the kill switch, Medvedev held on to the nerves to come back and win the next game and the championship in turn.
Meanwhile, Djokovic was at the brink of making history if he had won the title. He would become the first man to win all four majors in one year since Rod Laver in 1969. Laver was in attendance at Arthur Ashe Stadium.
The No. 1-ranked entered the match 27-0 in 2021 at the sport’s four most important tournaments but fatigue seemed to had set in as he kept conceding unforced errors, 38 in total.
He wasn't able to convert a break chance until it was too little, too late. In what has become his signature, Djokovic showed frustration, too, destroying his racket by pounding it three times against the court after one point, drawing boos from the Arthur Ashe Stadium crowd and a code violation from the chair umpire.
Currently, he remains tied with Roger Federer and Rafael Nadal with 20 major titles.