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| U | Santos de Guápiles | - | New York City FC | 0:2 (0:2) | ||
| R | New York City FC | - | Santos de Guápiles | 4:0 (2:0) | ||
| U: 16.02.2022 02:00 | R: 24.02.2022 00:00 | Winnaars: New York City FC | ||||
| U | Santos Laguna | - | CF Montréal | 1:0 (0:0) | ||
| R | CF Montréal | - | Santos Laguna | 3:0 (2:0) | ||
| U: 16.02.2022 04:00 | R: 24.02.2022 02:15 | Winnaars: CF Montréal | ||||
| U | Deportivo Guastatoya | - | Club León | 0:2 (0:2) | ||
| R | Club León | - | Deportivo Guastatoya | 1:0 (1:0) | ||
| U: 17.02.2022 00:00 | R: 23.02.2022 04:15 | Winnaars: Club León | ||||
| U | Forge FC | - | Cruz Azul | 0:1 (0:1) | ||
| R | Cruz Azul | - | Forge FC | 3:1 (3:1) | ||
| U: 17.02.2022 02:00 | R: 25.02.2022 02:30 | Winnaars: Cruz Azul | ||||
| U | Deportivo Saprissa | - | Pumas UNAM | 2:2 (1:1) | ||
| R | Pumas UNAM | - | Deportivo Saprissa | 4:1 (1:0) | ||
| U: 17.02.2022 04:00 | R: 24.02.2022 04:30 | Winnaars: Pumas UNAM | ||||
| U | Comunicaciones | - | Colorado Rapids | 1:0 (0:0) | ||
| R | Colorado Rapids | - | Comunicaciones | 3:4 (1:0, 1:0) d.p. | ||
| U: 18.02.2022 01:00 | R: 24.02.2022 02:15 | Winnaars: Comunicaciones | ||||
| U | Motagua | - | Seattle Sounders | 0:0 (0:0) | ||
| R | Seattle Sounders | - | Motagua | 5:0 (1:0) | ||
| U: 18.02.2022 03:00 | R: 25.02.2022 04:45 | Winnaars: Seattle Sounders | ||||
| U | Cavaly AS | - | New England Revolution | 0:3 Toeg. | ||
| R | New England Revolution | - | Cavaly AS | 3:0 Toeg. | ||
| U: 18.02.2022 23:30 | R: 23.02.2022 | Winnaars: New England Revolution | ||||
