| 11 May 21 | r04     | Metropolitanos F.C.Metropolitano | 0 - 1 | Atletico PRAtletico PR |
| 11 May 21 | r04 | BragantinoBragantino | 2 - 0 | EmelecEmelec |
| 12 May 21 | r04 | Montevideo City TorqueMontevideo Ci | 1 - 1 | IndependienteIndependiente |
| 12 May 21 | r04 | Talleres de CordobaTalleres de C | 0 - 0 | Deportes TolimaDeportes Toli |
| 12 May 21 | r04 | 12 de Octubre12 de Octubre | 1 - 2 | HuachipatoHuachipato |
| 12 May 21 | r04 | CearaCeara | 0 - 0 | Arsenal SarandiArsenal Saran |
| 13 May 21 | r04 | San LorenzoSan Lorenzo | 1 - 2 | Rosario CentralRosario Centr |
| 13 May 21 | r04 | BolivarBolivar | 2 - 2 | WilstermannWilstermann |
| 13 May 21 | r04 | Atletico GOAtletico GO | 0 - 0 | PalestinoPalestino |
| 13 May 21 | r04 | Club Deportivo GuabiráClub Deportiv | 0 - 1 | BahiaBahia |
| 13 May 21 | r04 | Aragua F.C.Aragua F.C. | 1 - 2 | La EquidadLa Equidad |
| 13 May 21 | r04 | GremioGremio | 3 - 1 | LanusLanus |
| 14 May 21 | r04 | SD AucasSD Aucas | 2 - 1 | FBC MelgarFBC Melgar |
| 14 May 21 | r04 | Club River Plate AsunciónClub River Pl | 2 - 1 | Sport HuancayoSport Huancay |
| 14 May 21 | r04 | PeñarolPeñarol | 4 - 0 | CorinthiansCorinthians |
| 14 May 21 | r04 | Club LibertadClub Libertad | 1 - 0 | Newells Old BoysNewells Old B |
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