After a poor run of form in the season's second stage, Bustos returned to replaced Célico.

Barcelona met second-stage winners Aucas in the season-long Serie A final which was played over two legs.

Tied 1–1 on aggregate, Barcelona won on penalties and advanced to the second stage (Match C5).

Tied 0–0 on aggregate, América Mineiro won on penalties and advanced to the group stage.

The draw for the group stage was held on 25 March 2022, 12:00 PYST (UTC−4), at the CONMEBOL Convention Centre in Luque, Paraguay.