| 2. Round | 01/05/2021 | CF Montréal | - | Columbus Crew | 0:0 | ||||
| 2. Round | 13/05/2021 | Toronto FC | - | Columbus Crew | 2:0 | ||||
| 2. Round | 16/05/2021 | New England Revolution | - | Columbus Crew | 1:0 | ||||
| 2. Round | 23/05/2021 | New York City FC | - | Columbus Crew | 1:2 | ||||
| 2. Round | 29/05/2021 | Columbus Crew | - | Toronto FC | 2:1 | ||||
| 3. Round | 20/06/2021 | Columbus Crew | - | Chicago Fire | 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 |  |
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| 4. Round | 24/07/2021 | Atlanta United FC | - | Columbus Crew | 0:1 | ||||
| 4. Round | 31/07/2021 | New York City FC | - | Columbus Crew | 4:1 | ||||
| 5. Round | 05/08/2021 | Columbus Crew | - | D.C. United | 2:4 | ||||
| 5. Round | 08/08/2021 | Columbus Crew | - | Atlanta United FC | 2:3 | ||||
| 5. Round | 15/08/2021 | Chicago Fire | - | Columbus Crew | 1:0 | ||||
| 5. Round | 21/08/2021 | Columbus Crew | - | Seattle Sounders | 1:2 | ||||
| 6. Round | 15/09/2021 | Columbus Crew | - | New York RB | 2:1 | ||||
| 6. Round | 19/09/2021 | New England Revolution | - | Columbus Crew | 1:1 | |
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| 6. Round | 26/09/2021 | Columbus Crew | - | CF Montréal | 2:1 | ||||
| 7. Round | 03/10/2021 | Philadelphia Union | - | Columbus Crew | 3:0 |
USA