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| H | Macará | - | Emelec | 2:2 (1:2) | ||
| R | Emelec | - | Macará | 2:0 (1:0) | ||
| H: 16.03.2021 23:15 | R: 07.04.2021 00:15 | Sieger: Emelec | ||||
| H | 12 de Octubre de Itauguá | - | Club Nacional | 0:0 (0:0) | ||
| R | Club Nacional | - | 12 de Octubre de Itauguá | 4:5 (0:0, 0:0) i.E. | ||
| H: 16.03.2021 23:15 | R: 07.04.2021 00:15 | Sieger: 12 de Octubre de Itauguá | ||||
| H | Deportes Tolima | - | Deportivo Cali | 3:0 (2:0) | ||
| R | Deportivo Cali | - | Deportes Tolima | 0:0 (0:0) | ||
| H: 17.03.2021 01:30 | R: 07.04.2021 02:30 | Sieger: Deportes Tolima | ||||
| H | Antofagasta | - | Huachipato | 0:1 (0:0) | ||
| R | Huachipato | - | Antofagasta | 3:0 (1:0) | ||
| H: 17.03.2021 01:30 | R: 07.04.2021 02:30 | Sieger: Huachipato | ||||
| H | CD Guabirá | - | Nacional Potosí | 4:1 (1:1) | ||
| R | Nacional Potosí | - | CD Guabirá | 1:2 (0:1) | ||
| H: 17.03.2021 23:15 | R: 08.04.2021 00:15 | Sieger: CD Guabirá | ||||
| H | Jorge Wilstermann | - | Atlético Palmaflor | 2:1 (2:0) | ||
| R | Atlético Palmaflor | - | Jorge Wilstermann | 1:2 (1:1) | ||
| H: 18.03.2021 01:30 | R: 08.04.2021 02:30 | Sieger: Jorge Wilstermann | ||||
| H | Universidad Técnica | - | Sport Huancayo | 0:1 (0:0) | ||
| R | Sport Huancayo | - | Universidad Técnica | 4:0 (2:0) | ||
| H: 18.03.2021 01:30 | R: 08.04.2021 02:30 | Sieger: Sport Huancayo | ||||
| H | Aragua FC | - | Mineros de Guayana | 0:1 (0:0) | ||
| R | Mineros de Guayana | - | Aragua FC | 1:2 (1:2) | ||
| H: 18.03.2021 01:30 | R: 08.04.2021 00:15 | Sieger: Aragua FC | ||||
| H | Aucas | - | Guayaquil City | 2:1 (1:1) | ||
| R | Guayaquil City | - | Aucas | 0:3 (0:3) | ||
| H: 18.03.2021 23:15 | R: 09.04.2021 00:15 | Sieger: Aucas | ||||
| H | Guaireña FC | - | River Plate | 1:2 (0:0) | ||
| R | River Plate | - | Guaireña FC | 4:2 (3:1) | ||
| H: 18.03.2021 23:15 | R: 09.04.2021 00:15 | Sieger: River Plate | ||||
| H | Metropolitanos FC | - | Academia Puerto Cabello | 2:0 (1:0) | ||
| R | Academia Puerto Cabello | - | Metropolitanos FC | 0:1 (0:1) | ||
| H: 18.03.2021 23:15 | R: 09.04.2021 00:15 | Sieger: Metropolitanos FC | ||||
| H | La Equidad | - | Deportivo Pasto | 1:2 (1:1) | ||
| R | Deportivo Pasto | - | La Equidad | 0:2 (0:2) | ||
| H: 19.03.2021 01:30 | R: 09.04.2021 02:30 | Sieger: La Equidad | ||||
| H | Mannucci | - | FBC Melgar | 1:2 (0:2) | ||
| R | FBC Melgar | - | Mannucci | 3:2 (2:1) | ||
| H: 19.03.2021 01:30 | R: 09.04.2021 02:30 | Sieger: FBC Melgar | ||||
| H | Cobresal | - | Palestino | 0:0 (0:0) | ||
| R | Palestino | - | Cobresal | 2:1 (1:1) | ||
| H: 19.03.2021 01:30 | R: 09.04.2021 02:30 | Sieger: Palestino | ||||
| H | Cerro Largo | - | Peñarol | 2:2 (0:1) | ||
| R | Peñarol | - | Cerro Largo | 4:1 (3:1) | ||
| H: 07.04.2021 02:30 | R: 14.04.2021 02:30 | Sieger: Peñarol | ||||
| H | Montevideo City Torque | - | Fénix | 0:0 (0:0) | ||
| R | Fénix | - | Montevideo City Torque | 0:2 (0:1) | ||
| H: 08.04.2021 00:15 | R: 15.04.2021 00:15 | Sieger: Montevideo City Torque | ||||
