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| 1st(1st leg) | Marathón | - | Portland Timbers | 2:2 (1:1) | ||
| 2nd (2nd leg) | Portland Timbers | - | Marathón | 5:0 (2:0) | ||
| 1st(1st leg): 06/04/2021 23:00 | 2nd (2nd leg): 14/04/2021 01:00 | Winner: Portland Timbers | ||||
| 1st(1st leg) | LD Alajuelense | - | Atlanta United FC | 0:1 (0:0) | ||
| 2nd (2nd leg) | Atlanta United FC | - | LD Alajuelense | 1:0 (0:0) | ||
| 1st(1st leg): 07/04/2021 01:00 | 2nd (2nd leg): 13/04/2021 23:00 | Winner: Atlanta United FC | ||||
| 1st(1st leg) | Arcahaie FC | - | Cruz Azul | 0:0 (0:0) | ||
| 2nd (2nd leg) | Cruz Azul | - | Arcahaie FC | 8:0 (3:0) | ||
| 1st(1st leg): 07/04/2021 03:00 | 2nd (2nd leg): 14/04/2021 03:00 | Winner: Cruz Azul | ||||
| 1st(1st leg) | Deportivo Saprissa | - | Philadelphia Union | 0:1 (0:1) | ||
| 2nd (2nd leg) | Philadelphia Union | - | Deportivo Saprissa | 4:0 (0:0) | ||
| 1st(1st leg): 07/04/2021 23:00 | 2nd (2nd leg): 15/04/2021 01:00 | Winner: Philadelphia Union | ||||
| 1st(1st leg) | Club León | - | Toronto FC | 1:1 (1:0) | ||
| 2nd (2nd leg) | Toronto FC | - | Club León | 2:1 (0:0) | ||
| 1st(1st leg): 08/04/2021 01:00 | 2nd (2nd leg): 14/04/2021 23:00 | Winner: Toronto FC | ||||
| 1st(1st leg) | Olimpia | - | CF América | 1:2 (0:2) | ||
| 2nd (2nd leg) | CF América | - | Olimpia | 0:1 (0:0) | ||
| 1st(1st leg): 08/04/2021 03:00 | 2nd (2nd leg): 15/04/2021 01:00 | Winner: CF América | ||||
| 1st(1st leg) | Real Estelí FC | - | Columbus Crew | 0:4 (0:4) | ||
| 2nd (2nd leg) | Columbus Crew | - | Real Estelí FC | 1:0 (0:0) | ||
| 1st(1st leg): 09/04/2021 01:00 | 2nd (2nd leg): 16/04/2021 01:00 | Winner: Columbus Crew | ||||
| 1st(1st leg) | CD Pantoja | - | CF Monterrey | 0:3 (0:2) | ||
| 2nd (2nd leg) | CF Monterrey | - | CD Pantoja | 3:1 (2:0) | ||
| 1st(1st leg): 09/04/2021 03:00 | 2nd (2nd leg): 16/04/2021 03:00 | Winner: CF Monterrey | ||||
