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| H | New York City FC | - | Comunicaciones | 3:1 (1:0) | ||
| R | Comunicaciones | - | New York City FC | 4:2 (1:1) | ||
| H: 09.03.2022 02:00 | R: 16.03.2022 01:00 | Sieger: New York City FC | ||||
| H | Seattle Sounders | - | Club León | 3:0 (2:0) | ||
| R | Club León | - | Seattle Sounders | 1:1 (0:1) | ||
| H: 09.03.2022 04:00 | R: 18.03.2022 01:30 | Sieger: Seattle Sounders | ||||
| H | New England Revolution | - | Pumas UNAM | 3:0 (1:0) | ||
| R | Pumas UNAM | - | New England Revolution | 3:0 (1:0) i.E. | ||
| H: 10.03.2022 02:00 | R: 17.03.2022 03:15 | Sieger: Pumas UNAM | ||||
| H | Cruz Azul | - | CF Montréal | 1:0 (1:0) | ||
| R | CF Montréal | - | Cruz Azul | 1:1 (0:1) | ||
| H: 10.03.2022 04:00 | R: 17.03.2022 01:00 | Sieger: Cruz Azul | ||||
