| 20 Apr 21 | r01     | Metropolitanos F.C.Metropolitano | 2 - 3 | FBC MelgarFBC Melgar |
| 20 Apr 21 | r01 | Atletico GOAtletico GO | 0 - 0 | Newells Old BoysNewells Old B |
| 21 Apr 21 | r01 | 12 de Octubre12 de Octubre | 1 - 0 | Rosario CentralRosario Centr |
| 21 Apr 21 | r01 | SD AucasSD Aucas | 0 - 1 | Atletico PRAtletico PR |
| 21 Apr 21 | r01 | San LorenzoSan Lorenzo | 0 - 1 | HuachipatoHuachipato |
| 21 Apr 21 | r01 | CearaCeara | 3 - 1 | WilstermannWilstermann |
| 22 Apr 21 | r01 | Montevideo City TorqueMontevideo Ci | 1 - 1 | BahiaBahia |
| 22 Apr 21 | r01 | Club Deportivo GuabiráClub Deportiv | 1 - 3 | IndependienteIndependiente |
| 22 Apr 21 | r01 | Talleres de CordobaTalleres de C | 1 - 2 | EmelecEmelec |
| 22 Apr 21 | r01 | BolivarBolivar | 2 - 1 | Arsenal SarandiArsenal Saran |
| 22 Apr 21 | r01 | BragantinoBragantino | 2 - 1 | Deportes TolimaDeportes Toli |
| 22 Apr 21 | r01 | GremioGremio | 2 - 1 | La EquidadLa Equidad |
| 22 Apr 21 | r01 | Aragua F.C.Aragua F.C. | 0 - 1 | LanusLanus |
| 23 Apr 21 | r01 | PeñarolPeñarol | 5 - 1 | Sport HuancayoSport Huancay |
| 23 Apr 21 | r01 | Club River Plate AsunciónClub River Pl | 0 - 0 | CorinthiansCorinthians |
| 23 Apr 21 | r01 | Club LibertadClub Libertad | 2 - 0 | PalestinoPalestino |
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