| 2021 Challenger de Santiago II | |
|---|---|
| Date | 4–10 October |
| Edition | 14th |
| Surface | Clay |
| Location | Santiago, Chile |
| Champions | |
| Singles | |
 Juan Pablo Varillas | |
| Doubles | |
 Diego Hidalgo /  Nicolás Jarry | |
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 |
|---|---|---|---|
 ARG | Juan Manuel Cerúndolo | 103 | 1 |
| ARG | Francisco Cerúndolo | 110 | 2 |
| PER | Juan Pablo Varillas | 117 | 3 |
 BOL | Hugo Dellien | 140 | 4 |
| ARG | Sebastián Báez | 143 | 5 |
| CHI | Marcelo Tomás Barrios Vera | 155 | 6 |
| ARG | Juan Ignacio Londero | 157 | 7 |
 BRA | Felipe Meligeni Alves | 202 | 8 |
The following players received wildcards into the singles main draw:
Diego Fernández Flores Gonzalo Lama Víctor NúñezThe 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:
Juan Pablo Varillas def. Sebastián Báez 6–4, 7–5. Diego Hidalgo / Nicolás Jarry def. Evan King / Max Schnur 6–3, 5–7, [10–6].
