The 2021 Internazionali di Tennis Città di Perugia was a professional tennis tournament played on clay courts. It was the sixth edition of the tournament which was part of the 2021 ATP Challenger Tour. It took place in Perugia, Italy between 5 and 11 July 2021.
| Country | Player | Rank1 | Seed | |
|---|---|---|---|---|
 Italy | Salvatore Caruso | 96 | 1 | |
 Slovakia | Andrej Martin | 111 | 2 | |
| Italy | Federico Gaio | 145 | 3 | |
 China | Zhang Zhizhen | 175 | 4 | |
| Italy | Thomas Fabbiano | 183 | 5 | |
 Kazakhstan | Dmitry Popko | 187 | 6 | |
 Argentina | Tomás Martín Etcheverry | 192 | 7 | |
| Argentina | Renzo Olivo | 193 | 8 |
The following players received wildcards into the singles main draw:
The following players received entry from the qualifying draw:
See main article: 2021 Internazionali di Tennis Città di Perugia – Singles.
Tomás Martín Etcheverry def. 
Vitaliy Sachko 7–5, 6–2.See main article: 2021 Internazionali di Tennis Città di Perugia – Doubles.
Vitaliy Sachko / Dominic Stricker def. Tomás Martín Etcheverry / Renzo Olivo 6–3, 5–7, [10–8].