Alexander Zverev defeated Matteo Berrettini in the final, 6–7(8–10), 6–4, 6–3 to win the men's singles tennis title at the 2021 Madrid Open.

[1] Novak Djokovic was the reigning champion from when the tournament was last held in 2019, but did not participate.

[2] Following the third-round eliminations of Daniil Medvedev and Stefanos Tsitsipas, respectively, a maiden Masters 1000 singles finalist from the bottom half of the draw was guaranteed; Berrettini went on to become that player.

Click on the seed number of a player to go to their draw section.

Seedings are based on ATP rankings as of 26 April 2021.