[1] The Columbus Crew were the defending MLS Cup champions, but failed to qualify for the playoffs after finishing ninth in the Eastern Conference.

Background colors denote playoff teams, with green also qualifying for the 2022 CONCACAF Champions League.

The higher-seeded teams in each match-up as determined by regular season ranking hosted the matches.

The higher-seeded teams in each conference as determined by regular season ranking hosted the matches.

The highest-ranked team remaining in the overall table (Portland Timbers) hosted the match.