| Champ: | Alexander Zverev |
| Runner: |  Matteo Berrettini |
| Score: | 6–7(8–10), 6–4, 6–3 |
| Draw: | 56 (8 / 4) |
| Seeds: | 16 |
| After Year: | 2022 |
| Before Year: | 2019 |
See main article: article and 2021 Mutua Madrid Open.
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. It was Zverev's fourth Masters 1000 title, his first since Madrid 2018, and his 15th career ATP Tour singles title overall. Berrettini was in contention to become the second Italian to be a Masters 1000 champion.[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.[3] [4]
The top eight seeds received a bye into the second round.
The following are the seeded players. Seedings are based on ATP rankings as of 26 April 2021. Rankings and points before are as of 3 May 2021.
| Seed | Rank | Player | Points before | Points defending | Points won | Points after | Status | |
|---|---|---|---|---|---|---|---|---|
| 1 | 2 |  Rafael Nadal | 9,810 | 360 | 180 | 9,630 | Quarterfinals lost to Alexander Zverev [5] | |
| 2 | 3 |  Daniil Medvedev | 9,700 | 10 | 90 | 9,780 | Third round lost to Cristian Garín [16] | |
| 3 | 4 |  Dominic Thiem | 8,365 | 360 | 360 | 8,365 | Semifinals lost to Alexander Zverev [5] | |
| 4 | 5 | Stefanos Tsitsipas | 7,910 | 390 | 90 | 7,610 | Third round lost to  Casper Ruud | |
| 5 | 6 | Alexander Zverev | 6,125 | 180 | 1,000 | 6,945 | Champion, defeated Matteo Berrettini [8] | |
| 6 | 8 | Andrey Rublev | 6,000 | 90 | 90 | 6,000 | Third round lost to  John Isner | |
| 7 | 9 |  Diego Schwartzman | 3,765 | 67 | 45 | 3,743 | Second round lost to Aslan Karatsev | |
| 8 | 10 | Matteo Berrettini | 3,493 | 45 | 600 | 4,048 | Runner-up, lost to Alexander Zverev [5] | |
| 9 | 11 | Roberto Bautista Agut | 3,090 | 10 | 45 | 3,125 | Second round lost to John Isner | |
| 10 | 12 | Pablo Carreño Busta | 3,015 | 10 | 10 | 3,015 | First round lost to | |
| 11 | 14 |  Denis Shapovalov | 2,820 | 10 | 45 | 2,855 | Second round lost to  Alexander Bublik | |
| 12 | 16 |  Hubert Hurkacz | 2,600 | 67 | 10 | 2,543 | First round lost to  John Millman | |
| 13 | 17 | Grigor Dimitrov | 2,576 | 10 | 10 | 2,576 | First round lost to Lloyd Harris | |
| 14 | 18 | Jannik Sinner | 2,524 | 24 | 45 | 2,545 | Second round lost to Alexei Popyrin [Q] | |
| 15 | 20 | Félix Auger-Aliassime | 2,418 | 32 | 10 | 2,396 | First round lost to Casper Ruud | |
| 16 | 22 | Cristian Garín | 2,215 | 45 | 180 | 2,350 | Quarterfinals lost to Matteo Berrettini [8] |
The following players received wildcards into the main draw:
The following players received entry from the qualifying draw:
Pablo Andújar Marco Cecchinato Federico Delbonis Marcos Giron
Pierre-Hugues Herbert Alexei Popyrin Carlos TabernerThe following player received entry as a lucky loser:
Tommy Paul Jérémy Chardy
Novak Djokovic → replaced by Alejandro Davidovich Fokina Miomir Kecmanović
David Goffin → replaced by Lloyd Harris Gaël Monfils → replaced by Guido Pella Milos Raonic → replaced by 
Yoshihito Nishioka Lorenzo Sonego → replaced by Dominik Koepfer Albert Ramos Viñolas