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| 1st(1st leg) | Macará | - | Emelec | 2:2 (1:2) | ||
| 2nd (2nd leg) | Emelec | - | Macará | 2:0 (1:0) | ||
| 1st(1st leg): 16/03/2021 22:15 | 2nd (2nd leg): 06/04/2021 23:15 | Winner: Emelec | ||||
| 1st(1st leg) | 12 de Octubre de Itauguá | - | Club Nacional | 0:0 (0:0) | ||
| 2nd (2nd leg) | Club Nacional | - | 12 de Octubre de Itauguá | 4:5 (0:0, 0:0) pso | ||
| 1st(1st leg): 16/03/2021 22:15 | 2nd (2nd leg): 06/04/2021 23:15 | Winner: 12 de Octubre de Itauguá | ||||
| 1st(1st leg) | Deportes Tolima | - | Deportivo Cali | 3:0 (2:0) | ||
| 2nd (2nd leg) | Deportivo Cali | - | Deportes Tolima | 0:0 (0:0) | ||
| 1st(1st leg): 17/03/2021 00:30 | 2nd (2nd leg): 07/04/2021 01:30 | Winner: Deportes Tolima | ||||
| 1st(1st leg) | Antofagasta | - | Huachipato | 0:1 (0:0) | ||
| 2nd (2nd leg) | Huachipato | - | Antofagasta | 3:0 (1:0) | ||
| 1st(1st leg): 17/03/2021 00:30 | 2nd (2nd leg): 07/04/2021 01:30 | Winner: Huachipato | ||||
| 1st(1st leg) | CD Guabirá | - | Nacional Potosí | 4:1 (1:1) | ||
| 2nd (2nd leg) | Nacional Potosí | - | CD Guabirá | 1:2 (0:1) | ||
| 1st(1st leg): 17/03/2021 22:15 | 2nd (2nd leg): 07/04/2021 23:15 | Winner: CD Guabirá | ||||
| 1st(1st leg) | Jorge Wilstermann | - | Atlético Palmaflor | 2:1 (2:0) | ||
| 2nd (2nd leg) | Atlético Palmaflor | - | Jorge Wilstermann | 1:2 (1:1) | ||
| 1st(1st leg): 18/03/2021 00:30 | 2nd (2nd leg): 08/04/2021 01:30 | Winner: Jorge Wilstermann | ||||
| 1st(1st leg) | Universidad Técnica | - | Sport Huancayo | 0:1 (0:0) | ||
| 2nd (2nd leg) | Sport Huancayo | - | Universidad Técnica | 4:0 (2:0) | ||
| 1st(1st leg): 18/03/2021 00:30 | 2nd (2nd leg): 08/04/2021 01:30 | Winner: Sport Huancayo | ||||
| 1st(1st leg) | Aragua FC | - | Mineros de Guayana | 0:1 (0:0) | ||
| 2nd (2nd leg) | Mineros de Guayana | - | Aragua FC | 1:2 (1:2) | ||
| 1st(1st leg): 18/03/2021 00:30 | 2nd (2nd leg): 07/04/2021 23:15 | Winner: Aragua FC | ||||
| 1st(1st leg) | Aucas | - | Guayaquil City | 2:1 (1:1) | ||
| 2nd (2nd leg) | Guayaquil City | - | Aucas | 0:3 (0:3) | ||
| 1st(1st leg): 18/03/2021 22:15 | 2nd (2nd leg): 08/04/2021 23:15 | Winner: Aucas | ||||
| 1st(1st leg) | Guaireña FC | - | River Plate | 1:2 (0:0) | ||
| 2nd (2nd leg) | River Plate | - | Guaireña FC | 4:2 (3:1) | ||
| 1st(1st leg): 18/03/2021 22:15 | 2nd (2nd leg): 08/04/2021 23:15 | Winner: River Plate | ||||
| 1st(1st leg) | Metropolitanos FC | - | Academia Puerto Cabello | 2:0 (1:0) | ||
| 2nd (2nd leg) | Academia Puerto Cabello | - | Metropolitanos FC | 0:1 (0:1) | ||
| 1st(1st leg): 18/03/2021 22:15 | 2nd (2nd leg): 08/04/2021 23:15 | Winner: Metropolitanos FC | ||||
| 1st(1st leg) | La Equidad | - | Deportivo Pasto | 1:2 (1:1) | ||
| 2nd (2nd leg) | Deportivo Pasto | - | La Equidad | 0:2 (0:2) | ||
| 1st(1st leg): 19/03/2021 00:30 | 2nd (2nd leg): 09/04/2021 01:30 | Winner: La Equidad | ||||
| 1st(1st leg) | Mannucci | - | FBC Melgar | 1:2 (0:2) | ||
| 2nd (2nd leg) | FBC Melgar | - | Mannucci | 3:2 (2:1) | ||
| 1st(1st leg): 19/03/2021 00:30 | 2nd (2nd leg): 09/04/2021 01:30 | Winner: FBC Melgar | ||||
| 1st(1st leg) | Cobresal | - | Palestino | 0:0 (0:0) | ||
| 2nd (2nd leg) | Palestino | - | Cobresal | 2:1 (1:1) | ||
| 1st(1st leg): 19/03/2021 00:30 | 2nd (2nd leg): 09/04/2021 01:30 | Winner: Palestino | ||||
| 1st(1st leg) | Cerro Largo | - | Peñarol | 2:2 (0:1) | ||
| 2nd (2nd leg) | Peñarol | - | Cerro Largo | 4:1 (3:1) | ||
| 1st(1st leg): 07/04/2021 01:30 | 2nd (2nd leg): 14/04/2021 01:30 | Winner: Peñarol | ||||
| 1st(1st leg) | Montevideo City Torque | - | Fénix | 0:0 (0:0) | ||
| 2nd (2nd leg) | Fénix | - | Montevideo City Torque | 0:2 (0:1) | ||
| 1st(1st leg): 07/04/2021 23:15 | 2nd (2nd leg): 14/04/2021 23:15 | Winner: Montevideo City Torque | ||||
