The 2021 Challenger de Santiago was a professional tennis tournament played on clay courts. It was the 13th edition of the tournament which was part of the 2021 ATP Challenger Tour. It took place in Santiago, Chile between 15 and 21 March 2021.
| Country | Player | Rank1 | Seed | |
|---|---|---|---|---|
 Spain | Roberto Carballés Baena | 97 | 1 | |
 Slovakia | Andrej Martin | 104 | 2 | |
| Pedro Sousa | 110 | 3 | ||
 Argentina | ||||
| Slovakia | Jozef Kovalík | 129 | 5 | |
| Daniel Altmaier | 143 | 6 | ||
 Belgium | Kimmer Coppejans | 165 | 7 | |
| Alejandro Tabilo | 168 | 8 |
The following players received wildcards into the singles main draw:
The following player received entry into the singles main draw as an alternate:
The following players received entry from the qualifying draw:
The following player received entry as a lucky loser:
See main article: 2021 Challenger de Santiago – Singles.
Sebastián Báez def. Marcelo Tomás Barrios Vera 6–3, 7–6(7–4).See main article: 2021 Challenger de Santiago – Doubles.
Luis David Martínez / Gonçalo Oliveira def. 
Rafael Matos / Felipe Meligeni Alves 7–5, 6–1.