[2] The draw for the first stage was held on 5 February 2021, 12:00 PYST (UTC−3), at the CONMEBOL Convention Centre in Luque, Paraguay.
If still tied, extra time will not be played, and a penalty shoot-out would be used to determine the winner (Regulations Article 2.4.2).
Tied 0–0 on aggregate, 12 de Octubre won on penalties and advanced to the group stage (PAR 1).
Montevideo City Torque won 2–0 on aggregate and advanced to the group stage (URU 1).
Tied 2–2 on aggregate, Aragua won on away goals and advanced to the group stage (VEN 2).