The 2021 San Marino Open was a professional tennis tournament played on clay courts. The 28th edition of the tournament, which was part of the 2021 ATP Challenger Tour, took place in City of San Marino, San Marino between 9 and 15 August 2021.
| Country | Player | Rank1 | Seed | |
|---|---|---|---|---|
 Italy | Marco Cecchinato | 84 | 1 | |
 France | Gilles Simon | 102 | 2 | |
| Italy | Salvatore Caruso | 111 | 3 | |
 Bolivia, Plurination;al State of | Hugo Dellien | 139 | 4 | |
| Italy | Federico Gaio | 147 | 5 | |
 Argentina | ||||
| Argentina | Sebastián Báez | 156 | 7 | |
| Blaž Rola | 173 | 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 player received entry into the singles main draw as an alternate:
The following players received entry from the qualifying draw:
Francesco Forti
Orlando Luz Manuel Mazza Julian OcleppoThe following player received entry as a lucky loser:
See main article: 2021 San Marino Open – Singles.
Orlando Luz 1–6, 6–2, 6–3.See main article: 2021 San Marino Open – Doubles.
Zdeněk Kolář / 
Luis David Martínez def. Rafael Matos / João Menezes 1–6, 6–3, [10–3].
