| Saturday, 2 October 2021 |
| Time/Result | Home | Away | Venue |
| 2-1 |
Austin |
Real Salt Lake | Q2 Stadium |
| 2-1 |
CF Montreal |
Atlanta | Stade Saputo |
| 2-1 |
Orlando City SC |
D.C. | Exploria Stadium |
| 0-1 |
FC Cincinnati |
New York | TQL Stadium |
| 0-0 |
FC Dallas |
Minnesota | Toyota Stadium |
| 3-0 |
Vancouver |
San Jose | BC Place Stadium |
| Sunday, 3 October 2021 |
| Time/Result | Home | Away | Venue |
| 0-0 |
New York City FC |
Nashville SC | Red Bull Arena |
| 4-2 |
Sporting KC |
Houston | Children's Mercy Park |
| 3-1 |
Toronto FC |
Chicago | BMO Field |
| 3-0 |
Philadelphia |
Columbus | Talen Energy Stadium |
| 1-0 |
Portland |
Inter Miami CF | Providence Park |
| 1-1 |
Los Angeles |
Los Angeles FC | Dignity Health Sports Park |
| 3-0 |
Seattle |
Colorado | CenturyLink Field |
| Saturday, 9 October 2021 |
| Time/Result | Home | Away | Venue |
| 1-0 |
New York |
Inter Miami CF | Red Bull Arena |
| 1-2 |
FC Cincinnati |
Philadelphia | TQL Stadium |
| 4-1 |
Seattle |
Vancouver | CenturyLink Field |
| Sunday, 10 October 2021 |
| Time/Result | Home | Away | Venue |
| 1-3 |
Minnesota |
Colorado | Allianz Field |
| Saturday, 16 October 2021 |
| Time/Result | Home | Away | Venue |
| 2-2 |
CF Montreal |
Philadelphia | Stade Saputo |
| 3-1 |
Los Angeles FC |
San Jose | Banc of California Stadium |
| 4-0 |
Columbus |
Inter Miami CF | Lower.com Field |
| 2-2 |
New England |
Chicago | Gillette Stadium |
| 0-0 |
D.C. |
Nashville SC | Audi Field |
| 0-2 |
Toronto FC |
Atlanta | BMO Field |
| 0-1 |
FC Cincinnati |
Orlando City SC | TQL Stadium |
| 2-1 |
Houston |
Seattle | BBVA Stadium |
| 0-1 |
Austin |
Minnesota | Q2 Stadium |
| 3-1 |
Real Salt Lake |
Colorado | Rio Tinto Stadium |
| 2-1 |
Los Angeles |
Portland | Dignity Health Sports Park |
| Sunday, 17 October 2021 |
| Time/Result | Home | Away | Venue |
| 1-0 |
New York |
New York City FC | Red Bull Arena |
| 2-1 |
Vancouver |
Sporting KC | BC Place Stadium |
| Wednesday, 20 October 2021 |
| Time/Result | Home | Away | Venue |
| 2-3 |
D.C. |
New England | Audi Field |
| 1-1 |
Orlando City SC |
CF Montreal | Exploria Stadium |
| 3-4 |
FC Cincinnati |
Chicago | TQL Stadium |
| 1-1 |
Atlanta |
New York City FC | Mercedes-Benz Stadium |
| 3-0 |
Inter Miami CF |
Toronto FC | Inter Miami CF Stadium |
| 2-3 |
FC Dallas |
Los Angeles FC | Toyota Stadium |
| 3-2 |
Minnesota |
Philadelphia | Allianz Field |
| 0-3 |
Houston |
Los Angeles | BBVA Stadium |
| 1-1 |
Nashville SC |
Columbus | Nissan Stadium |
| 1-1 |
Colorado |
Seattle | Dick's Sporting Goods Park |
| 2-3 |
Portland |
Vancouver | Providence Park |
| 4-0 |
San Jose |
Austin | Earthquakes Stadium |
| Saturday, 23 October 2021 |
| Time/Result | Home | Away | Venue |
| 1-2 |
Seattle |
Sporting KC | CenturyLink Field |
| 1-2 |
Columbus |
New York | Lower.com Field |
| 1-1 |
Toronto FC |
CF Montreal | BMO Field |
| 1-0 |
Philadelphia |
Nashville SC | Talen Energy Stadium |
| 6-0 |
New York City FC |
D.C. | Yankee Stadium |
| 1-0 |
Chicago |
Real Salt Lake | Soldier Field |
| 1-1 |
Minnesota |
Los Angeles FC | Allianz Field |
| 5-1 |
Inter Miami CF |
FC Cincinnati | Inter Miami CF Stadium |
| 2-0 |
Colorado |
Portland | Dick's Sporting Goods Park |
| 2-2 |
Los Angeles |
FC Dallas | Dignity Health Sports Park |
| 1-1 |
San Jose |
Vancouver | Earthquakes Stadium |
| Sunday, 24 October 2021 |
| Time/Result | Home | Away | Venue |
| 2-1 |
Austin |
Houston | Q2 Stadium |
| 2-2 |
Orlando City SC |
New England | Exploria Stadium |
| Tuesday, 26 October 2021 |
| Time/Result | Home | Away | Venue |
| 3-0 |
Los Angeles FC |
Seattle | Banc of California Stadium |
| Wednesday, 27 October 2021 |
| Time/Result | Home | Away | Venue |
| 1-0 |
New England |
Colorado | Gillette Stadium |
| 3-2 |
Columbus |
Orlando City SC | Lower.com Field |
| 1-0 |
D.C. |
New York | Audi Field |
| 2-2 |
Toronto FC |
Philadelphia | BMO Field |
| 1-0 |
New York City FC |
Chicago | Yankee Stadium |
| 3-6 |
FC Cincinnati |
Nashville SC | TQL Stadium |
| 2-1 |
Atlanta |
Inter Miami CF | Mercedes-Benz Stadium |
| 1-2 |
FC Dallas |
Real Salt Lake | Toyota Stadium |
| 2-0 |
Sporting KC |
Los Angeles | Children's Mercy Park |
| 2-1 |
Vancouver |
Minnesota | BC Place Stadium |
| 2-0 |
Portland |
San Jose | Providence Park |
| Saturday, 30 October 2021 |
| Time/Result | Home | Away | Venue |
| 1-3 |
Inter Miami CF |
New York City FC | Inter Miami CF Stadium |
| 3-4 |
Real Salt Lake |
San Jose | Rio Tinto Stadium |
| 1-0 |
New York |
CF Montreal | Red Bull Arena |
| 1-1 |
Atlanta |
Toronto FC | Mercedes-Benz Stadium |
| 1-3 |
D.C. |
Columbus | Audi Field |
| 2-1 |
FC Dallas |
Austin | Toyota Stadium |
| Sunday, 31 October 2021 |
| Time/Result | Home | Away | Venue |
| 2-1 |
Minnesota |
Sporting KC | Allianz Field |
| 0-1 |
Houston |
Colorado | BBVA Stadium |
| 1-1 |
Orlando City SC |
Nashville SC | Exploria Stadium |
| 2-0 |
Philadelphia |
FC Cincinnati | Talen Energy Stadium |
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