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| H | Everton | - | Monagas | 3:0 (2:0) | ||
| R | Monagas | - | Everton | 1:0 (0:0) | ||
| H: 22.02.2022 23:15 | R: 01.03.2022 23:15 | Sieger: Everton | ||||
| H | Millonarios | - | Fluminense RJ | 1:2 (1:1) | ||
| R | Fluminense RJ | - | Millonarios | 2:0 (0:0) | ||
| H: 23.02.2022 01:30 | R: 02.03.2022 01:30 | Sieger: Fluminense RJ | ||||
| H | Plaza Colonia | - | The Strongest | 2:0 (2:0) | ||
| R | The Strongest | - | Plaza Colonia | 3:0 (2:0) | ||
| H: 23.02.2022 01:30 | R: 02.03.2022 01:30 | Sieger: The Strongest | ||||
| H | Bolívar | - | Universidad Catolica | 1:1 (1:1) | ||
| R | Universidad Catolica | - | Bolívar | 2:0 (2:0) | ||
| H: 23.02.2022 23:15 | R: 02.03.2022 23:15 | Sieger: Universidad Catolica | ||||
| H | América - MG | - | Guaraní | 0:1 (0:0) | ||
| R | Guaraní | - | América - MG | 4:5 (2:0, 2:3) i.E. | ||
| H: 23.02.2022 23:15 | R: 02.03.2022 23:15 | Sieger: América - MG | ||||
| H | Audax Italiano | - | Estudiantes | 1:0 (1:0) | ||
| R | Estudiantes | - | Audax Italiano | 2:0 (1:0) | ||
| H: 24.02.2022 01:30 | R: 03.03.2022 01:30 | Sieger: Estudiantes | ||||
| H | Barcelona | - | Universitario de Deportes | 2:0 (0:0) | ||
| R | Universitario de Deportes | - | Barcelona | 0:1 (0:0) | ||
| H: 24.02.2022 01:30 | R: 03.03.2022 01:30 | Sieger: Barcelona | ||||
| H | Club Olimpia | - | Atlético Nacional | 3:1 (1:0) | ||
| R | Atlético Nacional | - | Club Olimpia | 1:1 (0:0) | ||
| H: 25.02.2022 01:30 | R: 04.03.2022 01:30 | Sieger: Club Olimpia | ||||
