| Date: | 8–14 November |
| Edition: | 17th |
| Surface: | Hard (Indoor) |
| Location: | Knoxville, United States |
| Champs: |  Christopher Eubanks |
| Champd: |  Malek Jaziri / Blaž Rola |
| Before Year: | 2019 |
The 2021 Knoxville Challenger was a professional tennis tournament played on indoor hard courts. It was the seventeenth edition of the tournament which was part of the 2021 ATP Challenger Tour. It took place in Knoxville, United States between 8 and 14 November 2021.
| Country | Player | Rank1 | Seed | |
|---|---|---|---|---|
| Tennys Sandgren | 93 | 1 | ||
| Daniel Altmaier | 106 | 2 | ||
| Vasek Pospisil | 113 | 3 | ||
| Mitchell Krueger | 148 | 4 | ||
| Jack Sock | 153 | 5 | ||
| J. J. Wolf | 159 | 6 | ||
| Dmitry Popko | 171 | 7 | ||
| Bjorn Fratangelo | 172 | 8 |
The following players received wildcards into the singles main draw:
The 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 Knoxville Challenger – Singles.
Christopher Eubanks def. Daniel Altmaier 6–3, 6–4.See main article: 2021 Knoxville Challenger – Doubles.
Malek Jaziri / Blaž Rola def. 
Hans Hach Verdugo / Miguel Ángel Reyes-Varela 3–6, 6–3, [10–5].
