| Date: | 30 August – 5 September |
| Edition: | 15th |
| Surface: | Clay |
| Location: | Como, Italy |
| Champs: |  Juan Manuel Cerúndolo |
| Champd: |  Rafael Matos / Felipe Meligeni Alves |
| Before Year: | 2019 |
The 2021 Città di Como Challenger was a professional tennis tournament played on clay courts. It was the fifteenth edition of the tournament which was part of the 2021 ATP Challenger Tour. It took place in Como, Italy between 30 August and 5 September 2021.
| Country | Player | Rank1 | Seed | |
|---|---|---|---|---|
| Daniel Altmaier | 106 | 1 | ||
 Slovakia | Jozef Kovalík | 121 | 2 | |
| Slovakia | Andrej Martin | 122 | 3 | |
| Argentina | Juan Manuel Cerúndolo | 135 | 4 | |
 Italy | Federico Gaio | 159 | 5 | |
 India | Sumit Nagal | 165 | 6 | |
| Marc-Andrea Hüsler | 170 | 7 | ||
| Italy |
The following players received wildcards into the singles main draw:
Flavio Cobolli Francesco Forti Federico IannacconeThe following players received entry into the singles main draw using protected rankings:
The following players received entry into the singles main draw as special exempts:
The following players received entry into the singles main draw as alternates:
The following players received entry from the qualifying draw:
The following players received entry as lucky losers:
See main article: 2021 Città di Como Challenger – Singles.
Juan Manuel Cerúndolo def. Gian Marco Moroni 7–5, 7–6(9–7).See main article: 2021 Città di Como Challenger – Doubles.
Rafael Matos / Felipe Meligeni Alves def. 
Luis David Martínez / Andrea Vavassori 6–7(2–7), 6–4, [10–6].
