The 2021 Challenger de Santiago II was a professional tennis tournament played on clay courts. It was the 14th edition of the tournament which was part of the 2021 ATP Challenger Tour. It took place in Santiago, Chile between 4 and 10 October 2021.
| Country | Player | Rank1 | Seed | |
|---|---|---|---|---|
 Argentina | Juan Manuel Cerúndolo | 103 | 1 | |
| Argentina | Francisco Cerúndolo | 110 | 2 | |
 Peru | Juan Pablo Varillas | 117 | 3 | |
 Bolivia, Plurination;al State of | Hugo Dellien | 140 | 4 | |
| Argentina | Sebastián Báez | 143 | 5 | |
| Marcelo Tomás Barrios Vera | 155 | 6 | ||
| Argentina | Juan Ignacio Londero | 157 | 7 | |
 Brazil | Felipe Meligeni Alves | 202 | 8 |
The following players received wildcards into the singles main draw:
The following players received entry into the singles main draw using protected rankings:
The following players received entry into the singles main draw as alternates:
The following players received entry from the qualifying draw:
Nicolás Álvarez
Oliver Crawford Facundo Díaz Acosta
Alexis GautierThe following player received entry as a lucky loser:
See main article: 2021 Challenger de Santiago II – Singles.
Juan Pablo Varillas def. Sebastián Báez 6–4, 7–5.See main article: 2021 Challenger de Santiago II – Doubles.
Diego Hidalgo / Nicolás Jarry def. Evan King / Max Schnur 6–3, 5–7, [10–6].
