| # | Squadra | PG | V | P | S | GF | GC | DG | Pts. |
|---|---|---|---|---|---|---|---|---|---|
| 1 | New England | 30 | 20 | 6 | 4 | 59 | 36 | +23 | 66 |
| 2 | Nashville SC | 29 | 11 | 15 | 3 | 46 | 26 | +20 | 48 |
| 3 | Philadelphia Union | 29 | 12 | 10 | 7 | 40 | 29 | +11 | 46 |
| 4 | Orlando City | 29 | 12 | 9 | 8 | 42 | 41 | +1 | 45 |
| 5 | Atlanta United | 29 | 11 | 9 | 9 | 39 | 33 | +6 | 42 |
| 6 | D.C. United | 29 | 12 | 5 | 12 | 49 | 41 | +8 | 41 |
| 7 | Montréal | 29 | 11 | 8 | 10 | 42 | 39 | +3 | 41 |
| 8 | New York City | 29 | 11 | 7 | 11 | 44 | 33 | +11 | 40 |
| 9 | New York RB | 29 | 11 | 7 | 11 | 35 | 30 | +5 | 40 |
| 10 | Columbus Crew | 29 | 10 | 7 | 12 | 36 | 39 | -3 | 37 |
| 11 | Inter Miami | 29 | 9 | 5 | 15 | 25 | 47 | -22 | 32 |
| 12 | Chicago Fire | 30 | 7 | 7 | 16 | 31 | 48 | -17 | 28 |
| 13 | Toronto | 29 | 6 | 7 | 16 | 34 | 56 | -22 | 25 |
| 14 | Cincinnati | 29 | 4 | 8 | 17 | 29 | 55 | -26 | 20 |
| 2021. Ottobre 21. giovedì | ||
| Cincinnati | 00:30 | Chicago Fire |
| D.C. United | 00:30 | New England |
| Atlanta United | 00:30 | New York City |
| Inter Miami | 00:30 | Toronto |
| Orlando City | 00:30 | Montréal |
| Dallas | 01:00 | Los Angeles |
| Minnesota United | 01:00 | Philadelphia Union |
| Nashville SC | 01:30 | Columbus Crew |
| Houston Dynamo | 01:30 | LA Galaxy |
| Colorado Rapids | 02:00 | Seattle Sounders |
| Portland Timbers | 03:00 | Vancouver Whitecaps FC |
| SJ Earthquakes | 03:30 | Austin |
| 2021. Ottobre 23. sabato | ||
| Seattle Sounders | 20:30 | Sporting KC |
| 2021. Ottobre 18. lunedì | ||
| Vancouver Whitecaps FC | 2 - 1 | Sporting KC |
| 2021. Ottobre 17. domenica | ||
| New York RB | 1 - 0 | New York City |
| LA Galaxy | 2 - 1 | Portland Timbers |
| Real Salt Lake | 3 - 1 | Colorado Rapids |
| Austin | 0 - 1 | Minnesota United |
| Houston Dynamo | 2 - 1 | Seattle Sounders |
| Cincinnati | 0 - 1 | Orlando City |
| Toronto | 0 - 2 | Atlanta United |
| D.C. United | 0 - 0 | Nashville SC |
| New England | 2 - 2 | Chicago Fire |
| 2021. Ottobre 16. sabato | ||
| Columbus Crew | 4 - 0 | Inter Miami |
| Los Angeles | 3 - 1 | SJ Earthquakes |
| Montréal | 2 - 2 | Philadelphia Union |
| 2021. Ottobre 10. domenica | ||
| Minnesota United | 1 - 3 | Colorado Rapids |
| Seattle Sounders | 4 - 1 | Vancouver Whitecaps FC |
| Cincinnati | 1 - 2 | Philadelphia Union |
| 2021. Ottobre 9. sabato | ||
| New York RB | 1 - 0 | Inter Miami |
| 2021. Ottobre 4. lunedì | ||
| Seattle Sounders | 3 - 0 | Colorado Rapids |
| LA Galaxy | 1 - 1 | Los Angeles |
