[2] The draw for the first stage was held on 20 December 2021, 12:00 PYST (UTC−3), at the CONMEBOL Convention Centre in Luque, Paraguay.
If tied on aggregate, extra time was not played, and a penalty shoot-out was used to determine the winner (Regulations Article 2.4.2).
Tied 2–2 on aggregate, Deportes Antofagasta won on penalties and advanced to the group stage (CHI 1).
Unión La Calera won 2–1 on aggregate and advanced to the group stage (CHI 2).
Tied 3–3 on aggregate, Independiente Medellín won on penalties and advanced to the group stage (COL 2).