| Date: | 26 April – 2 May |
| Edition: | 13th |
| Surface: | Clay |
| Location: | Rome, Italy |
| Champs: |  Juan Manuel Cerúndolo |
| Champd: |  Sadio Doumbia / Fabien Reboul |
| Before Year: | 2021 |
| Before Name: | Garden Open |
| Main Name: | Garden Open |
| After Name: | Garden Open |
The 2021 Garden Open II was a professional tennis tournament played on clay courts. It was the thirteenth edition of the tournament which was part of the 2021 ATP Challenger Tour. It took place in Rome, Italy between 26 April and 2 May 2021.
| Country | Player | Rank1 | Seed | |
|---|---|---|---|---|
 Bosnia and Herzegovina | Damir Džumhur | 116 | 1 | |
 Bolivia, Plurination;al State of | Hugo Dellien | 125 | 2 | |
 Italy | Federico Gaio | 138 | 3 | |
 Serbia | Danilo Petrović | 157 | 4 | |
| France | Hugo Gaston | 158 | 5 | |
| Italy | Paolo Lorenzi | 159 | 6 | |
 Peru | Juan Pablo Varillas | 160 | 7 | |
| Italy | Alessandro Giannessi | 165 | 8 |
The following players received wildcards into the singles main draw:
The following player received entry into the singles main draw as a special exempt:
The following player received entry into the singles main draw using a protected ranking:
The following player received entry into the singles main draw as an alternate:
The following players received entry from the qualifying draw:
See main article: 2021 Garden Open II – Singles.
Juan Manuel Cerúndolo def. Flavio Cobolli 6–2, 3–6, 6–3.See main article: 2021 Garden Open II – Doubles.
Sadio Doumbia / Fabien Reboul def. Guido Andreozzi / Guillermo Durán 7–5, 6–3.
