| 03 May 22 | r04     | CA River PlateCA River Plat | 1 - 2 | FBC MelgarFBC Melgar |
| 03 May 22 | r04 | CuiabaCuiaba | 1 - 2 | Racing ClubRacing Club |
| 04 May 22 | r04 | 9 de Octubre9 de Octubre | 3 - 2 | Independiente MedellínIndependiente |
| 04 May 22 | r04 | CearaCeara | 3 - 0 | Real Esppor ClubReal Esppor C |
| 04 May 22 | r04 | General CaballeroGeneral Cabal | 0 - 4 | IndependienteIndependiente |
| 04 May 22 | r04 | Metropolitanos F.C.Metropolitano | 0 - 1 | WanderersWanderers |
| 04 May 22 | r04 | Atletico GOAtletico GO | 3 - 2 | Defensa y JusticiaDefensa y Jus |
| 04 May 22 | r04 | Deportes AntofagastaDeportes Anto | 1 - 2 | LDU QuitoLDU Quito |
| 05 May 22 | r04 | Barcelona SCBarcelona SC | 1 - 1 | LanusLanus |
| 05 May 22 | r04 | FluminenseFluminense | 2 - 1 | Atlético JuniorAtlético Juni |
| 05 May 22 | r04 | Everton de Viña del MarEverton de Vi | 0 - 0 | Sao PauloSao Paulo |
| 05 May 22 | r04 | Guaireña FCGuaireña FC | 1 - 1 | InternacionalInternacional |
| 05 May 22 | r04 | UnionUnion | 2 - 0 | Oriente PetroleroOriente Petro |
| 06 May 22 | r04 | BanfieldBanfield | 0 - 1 | Unión La CaleraUnión La Cale |
| 06 May 22 | r04 | Universidad Católica del Universidad C | 0 - 1 | Santos FCSantos FC |
| 06 May 22 | r04 | Ayacucho FCAyacucho FC | 0 - 0 | WilstermannWilstermann |
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