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| 1st(1st leg) | Everton | - | Monagas | 3:0 (2:0) | ||
| 2nd (2nd leg) | Monagas | - | Everton | 1:0 (0:0) | ||
| 1st(1st leg): 22/02/2022 22:15 | 2nd (2nd leg): 01/03/2022 22:15 | Winner: Everton | ||||
| 1st(1st leg) | Millonarios | - | Fluminense RJ | 1:2 (1:1) | ||
| 2nd (2nd leg) | Fluminense RJ | - | Millonarios | 2:0 (0:0) | ||
| 1st(1st leg): 23/02/2022 00:30 | 2nd (2nd leg): 02/03/2022 00:30 | Winner: Fluminense RJ | ||||
| 1st(1st leg) | Plaza Colonia | - | The Strongest | 2:0 (2:0) | ||
| 2nd (2nd leg) | The Strongest | - | Plaza Colonia | 3:0 (2:0) | ||
| 1st(1st leg): 23/02/2022 00:30 | 2nd (2nd leg): 02/03/2022 00:30 | Winner: The Strongest | ||||
| 1st(1st leg) | Bolívar | - | Universidad Catolica | 1:1 (1:1) | ||
| 2nd (2nd leg) | Universidad Catolica | - | Bolívar | 2:0 (2:0) | ||
| 1st(1st leg): 23/02/2022 22:15 | 2nd (2nd leg): 02/03/2022 22:15 | Winner: Universidad Catolica | ||||
| 1st(1st leg) | América - MG | - | Guaraní | 0:1 (0:0) | ||
| 2nd (2nd leg) | Guaraní | - | América - MG | 4:5 (2:0, 2:3) pso | ||
| 1st(1st leg): 23/02/2022 22:15 | 2nd (2nd leg): 02/03/2022 22:15 | Winner: América - MG | ||||
| 1st(1st leg) | Audax Italiano | - | Estudiantes | 1:0 (1:0) | ||
| 2nd (2nd leg) | Estudiantes | - | Audax Italiano | 2:0 (1:0) | ||
| 1st(1st leg): 24/02/2022 00:30 | 2nd (2nd leg): 03/03/2022 00:30 | Winner: Estudiantes | ||||
| 1st(1st leg) | Barcelona | - | Universitario de Deportes | 2:0 (0:0) | ||
| 2nd (2nd leg) | Universitario de Deportes | - | Barcelona | 0:1 (0:0) | ||
| 1st(1st leg): 24/02/2022 00:30 | 2nd (2nd leg): 03/03/2022 00:30 | Winner: Barcelona | ||||
| 1st(1st leg) | Club Olimpia | - | Atlético Nacional | 3:1 (1:0) | ||
| 2nd (2nd leg) | Atlético Nacional | - | Club Olimpia | 1:1 (0:0) | ||
| 1st(1st leg): 25/02/2022 00:30 | 2nd (2nd leg): 04/03/2022 00:30 | Winner: Club Olimpia | ||||
