| Date: | 1–7 November |
| Edition: | 12th |
| Surface: | Hard (indoor) |
| Location: | Charlottesville, United States |
| Champs: |  Stefan Kozlov |
| Champd: | William Blumberg / Max Schnur |
| Before Year: | 2019 |
The 2021 Charlottesville Men's Pro Challenger was a professional tennis tournament played on indoor hard courts. It was the twelfth edition of the tournament which was part of the 2021 ATP Challenger Tour, taking place in Charlottesville, United States from November 1 to 7, 2021.
| Country | Player | Rank1 | Seed | |
|---|---|---|---|---|
 Canada | Vasek Pospisil | 85 | 1 | |
 Japan | Taro Daniel | 120 | 2 | |
| Mitchell Krueger | 147 | 3 | ||
| Jack Sock | 152 | 4 | ||
 Kazakhstan | Dmitry Popko | 162 | 5 | |
| Jason Jung | 166 | 6 | ||
| Bjorn Fratangelo | 172 | 7 | ||
| Blaž Rola | 177 | 8 |
The following players received wildcards into the singles main draw:
Martin Damm Emilio NavaThe following player received entry into the singles main draw using a protected ranking:
The following players received entry into the singles main draw as alternates:
The following players received entry from the qualifying draw:
See main article: 2021 Charlottesville Men's Pro Challenger – Singles.
Stefan Kozlov def. 
Aleksandar Vukic 6–2, 6–3.See main article: 2021 Charlottesville Men's Pro Challenger – Doubles.
William Blumberg / Max Schnur def. Treat Huey / Frederik Nielsen 3–6, 6–1, [14–12].