| 12 Apr 22 | r02     | Real Esppor ClubReal Esppor C | 0 - 2 | CearaCeara |
| 12 Apr 22 | r02 | Oriente PetroleroOriente Petro | 1 - 3 | UnionUnion |
| 13 Apr 22 | r02 | Defensa y JusticiaDefensa y Jus | 0 - 1 | Atletico GOAtletico GO |
| 13 Apr 22 | r02 | LDU QuitoLDU Quito | 4 - 0 | Deportes AntofagastaDeportes Anto |
| 13 Apr 22 | r02 | IndependienteIndependiente | 2 - 0 | General CaballeroGeneral Cabal |
| 13 Apr 22 | r02 | FBC MelgarFBC Melgar | 2 - 0 | CA River PlateCA River Plat |
| 13 Apr 22 | r02 | Santos FCSantos FC | 3 - 2 | Universidad Católica del Universidad C |
| 13 Apr 22 | r02 | Racing ClubRacing Club | 2 - 0 | CuiabaCuiaba |
| 14 Apr 22 | r02 | WilstermannWilstermann | 0 - 2 | Ayacucho FCAyacucho FC |
| 14 Apr 22 | r02 | Atlético JuniorAtlético Juni | 3 - 0 | FluminenseFluminense |
| 14 Apr 22 | r02 | WanderersWanderers | 1 - 1 | Metropolitanos F.C.Metropolitano |
| 14 Apr 22 | r02 | Unión La CaleraUnión La Cale | 1 - 0 | BanfieldBanfield |
| 14 Apr 22 | r02 | Sao PauloSao Paulo | 2 - 0 | Everton de Viña del MarEverton de Vi |
| 15 Apr 22 | r02 | LanusLanus | 3 - 1 | Barcelona SCBarcelona SC |
| 15 Apr 22 | r02 | Independiente MedellínIndependiente | 2 - 1 | 9 de Octubre9 de Octubre |
| 15 Apr 22 | r02 | InternacionalInternacional | 1 - 1 | Guaireña FCGuaireña FC |
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