| 04 May 21 | r03     | BahiaBahia | 2 - 2 | IndependienteIndependiente |
| 04 May 21 | r03 | Metropolitanos F.C.Metropolitano | 3 - 2 | SD AucasSD Aucas |
| 05 May 21 | r03 | FBC MelgarFBC Melgar | 1 - 0 | Atletico PRAtletico PR |
| 05 May 21 | r03 | PalestinoPalestino | 0 - 1 | Newells Old BoysNewells Old B |
| 05 May 21 | r03 | HuachipatoHuachipato | 1 - 1 | Rosario CentralRosario Centr |
| 05 May 21 | r03 | Montevideo City TorqueMontevideo Ci | 4 - 0 | Club Deportivo GuabiráClub Deportiv |
| 05 May 21 | r03 | BolivarBolivar | 0 - 0 | CearaCeara |
| 06 May 21 | r03 | BragantinoBragantino | 0 - 1 | Talleres de CordobaTalleres de C |
| 06 May 21 | r03 | Arsenal SarandiArsenal Saran | 3 - 0 | WilstermannWilstermann |
| 06 May 21 | r03 | Club LibertadClub Libertad | 1 - 2 | Atletico GOAtletico GO |
| 06 May 21 | r03 | GremioGremio | 8 - 0 | Aragua F.C.Aragua F.C. |
| 07 May 21 | r03 | San LorenzoSan Lorenzo | 1 - 1 | 12 de Octubre12 de Octubre |
| 07 May 21 | r03 | Sport HuancayoSport Huancay | 0 - 3 | CorinthiansCorinthians |
| 07 May 21 | r03 | PeñarolPeñarol | 3 - 0 | Club River Plate AsunciónClub River Pl |
| 07 May 21 | r03 | La EquidadLa Equidad | 0 - 1 | LanusLanus |
| 08 May 21 | r03 | Deportes TolimaDeportes Toli | 1 - 1 | EmelecEmelec |
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