| Champ: |  Matteo Berrettini |
| Score: | 6–1, 3–6, 7–6(7–0) |
| Edition: | 5th |
| Before Year: | 2012 |
| After Name: | Serbia Open – Singles |
| Draw: | 28 (4 Q/ 3 WC) |
| Seeds: | 8 |
See main article: article and 2021 Serbia Open.
Matteo Berrettini defeated Aslan Karatsev in the final, 6–1, 3–6, 7–6(7–0) to win the men's singles tennis title at the 2021 Serbia Open.[1]
Andreas Seppi was the reigning champion from when the event was last held in 2012, but he decided not to participate this year.[2]
The top four seeds received a bye into the second round.