| Champ: |  Ilya Ivashka |
| Runner: |  Mikael Ymer |
| Score: | 6–0, 6–2 |
| Draw: | 48 (4 / 4) |
| Seeds: | 16 |
| Edition: | 52nd |
| Before Year: | 2019 |
| Type: | singles doubles |
See main article: article and 2021 Winston-Salem Open.
Hubert Hurkacz was the reigning champion from when the tournament was last held in 2019, but chose not to participate this year.
Ilya Ivashka won his maiden ATP Tour title, defeating Mikael Ymer in the final, 6–0, 6–2. Ivashka became the first Belarusian man to win an ATP singles title since Max Mirnyi in 2003, while Ymer became the first Swedish man to reach an ATP singles final since Robin Söderling in 2011.[1]
All seeds receive a bye into the second round.