Daniil Medvedev defeated Novak Djokovic in the final, 6–4, 6–4, 6–4 to win the men's singles tennis title at the 2021 US Open.

Djokovic was aiming to become the second man in the Open Era, after Rod Laver in 1969, to complete a Grand Slam.

[2] He was also attempting to win an outright record 21st major singles title and surpass his Big Three counterparts, Roger Federer and Rafael Nadal.

3 Stefanos Tsitsipas in the third round, Carlos Alcaraz became the youngest man to beat a top 3 ranked-player in singles at the US Open since the inception of the ATP rankings in 1973.

[4] Van de Zandschulp was the first Dutchman to reach a singles major quarterfinal since Sjeng Schalken at the 2004 Wimbledon Championships and the first qualifier to do so at the US Open since Gilles Müller in 2008.