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| 1st(1st leg) | Santos de Guápiles | - | New York City FC | 0:2 (0:2) | ||
| 2nd (2nd leg) | New York City FC | - | Santos de Guápiles | 4:0 (2:0) | ||
| 1st(1st leg): 16/02/2022 01:00 | 2nd (2nd leg): 23/02/2022 23:00 | Winner: New York City FC | ||||
| 1st(1st leg) | Santos Laguna | - | CF Montréal | 1:0 (0:0) | ||
| 2nd (2nd leg) | CF Montréal | - | Santos Laguna | 3:0 (2:0) | ||
| 1st(1st leg): 16/02/2022 03:00 | 2nd (2nd leg): 24/02/2022 01:15 | Winner: CF Montréal | ||||
| 1st(1st leg) | Deportivo Guastatoya | - | Club León | 0:2 (0:2) | ||
| 2nd (2nd leg) | Club León | - | Deportivo Guastatoya | 1:0 (1:0) | ||
| 1st(1st leg): 16/02/2022 23:00 | 2nd (2nd leg): 23/02/2022 03:15 | Winner: Club León | ||||
| 1st(1st leg) | Forge FC | - | Cruz Azul | 0:1 (0:1) | ||
| 2nd (2nd leg) | Cruz Azul | - | Forge FC | 3:1 (3:1) | ||
| 1st(1st leg): 17/02/2022 01:00 | 2nd (2nd leg): 25/02/2022 01:30 | Winner: Cruz Azul | ||||
| 1st(1st leg) | Deportivo Saprissa | - | Pumas UNAM | 2:2 (1:1) | ||
| 2nd (2nd leg) | Pumas UNAM | - | Deportivo Saprissa | 4:1 (1:0) | ||
| 1st(1st leg): 17/02/2022 03:00 | 2nd (2nd leg): 24/02/2022 03:30 | Winner: Pumas UNAM | ||||
| 1st(1st leg) | Comunicaciones | - | Colorado Rapids | 1:0 (0:0) | ||
| 2nd (2nd leg) | Colorado Rapids | - | Comunicaciones | 3:4 (1:0, 1:0) pso | ||
| 1st(1st leg): 18/02/2022 00:00 | 2nd (2nd leg): 24/02/2022 01:15 | Winner: Comunicaciones | ||||
| 1st(1st leg) | Motagua | - | Seattle Sounders | 0:0 (0:0) | ||
| 2nd (2nd leg) | Seattle Sounders | - | Motagua | 5:0 (1:0) | ||
| 1st(1st leg): 18/02/2022 02:00 | 2nd (2nd leg): 25/02/2022 03:45 | Winner: Seattle Sounders | ||||
| 1st(1st leg) | Cavaly AS | - | New England Revolution | 0:3 dec. | ||
| 2nd (2nd leg) | New England Revolution | - | Cavaly AS | 3:0 dec. | ||
| 1st(1st leg): 18/02/2022 22:30 | 2nd (2nd leg): 23/02/2022 | Winner: New England Revolution | ||||
