The 2021 Challenger de Santiago III was a professional tennis tournament played on clay courts. It was the 15th edition of the tournament which was part of the 2021 ATP Challenger Tour. It took place in Santiago, Chile between 11 and 17 October 2021.
| Country | Player | Rank1 | Seed | |
|---|---|---|---|---|
 Argentina | Juan Manuel Cerúndolo | 103 | 1 | |
| Argentina | Francisco Cerúndolo | 110 | 2 | |
 Peru | Juan Pablo Varillas | 127 | 3 | |
 Brazil | Thiago Seyboth Wild | 129 | 4 | |
| Argentina | Sebastián Báez | 140 | 5 | |
| Marcelo Tomás Barrios Vera | 154 | 6 | ||
| Argentina | Juan Ignacio Londero | 157 | 7 | |
 France | Enzo Couacaud | 189 | 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 players received entry into the singles main draw as alternates:
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 III – Singles.
Sebastián Báez def. Felipe Meligeni Alves 3–6, 7–6(8–6), 6–1.See main article: 2021 Challenger de Santiago III – Doubles.
Evan King / Max Schnur def. 
Hans Hach Verdugo / Miguel Ángel Reyes-Varela 3–6, 7–6(7–3), [16–14].
