| 2. Round | 01/05/2021 | CF Montréal | - | Columbus Crew | 0:0 | ||||
| 2. Round | 13/05/2021 | Toronto FC | - | Columbus Crew | 2:0 | ||||
| 4. Round | 10/07/2021 | FC Cincinnati | - | Columbus Crew | 2:2 | ||||
| 4. Round | 18/07/2021 | Columbus Crew | - | New York City FC | 2:1 | ||||
| 6. Round | 05/09/2021 | Orlando City | - | Columbus Crew | 3:2 | ||||
| 6. Round | 19/09/2021 | New England Revolution | - | Columbus Crew | 1:1 |  |
USA
Italy