The Columbus Crew were the only American team to qualify for the Championship Round of the 2009–10 CONCACAF Champions League, the only portion of the competition to occur in the 2010 calendar year.

[17] The Columbus Crew, Real Salt Lake, Los Angeles Galaxy, and Seattle Sounders FC qualified for the 2010–11 CONCACAF Champions League.

[19] Los Angeles, however, holders of the best record in Major League Soccer at the time of their matchup, were defeated 4–1 at the Home Depot Center.

The Columbus Crew, Real Salt Lake, and Seattle Sounders FC each qualified for the group stage.

The Crew hosted Municipal in their first match and won 1–0, the goal scored on a strong individual effort by Emmanuel Ekpo.

[25] In their second match, Columbus nearly held on for a scoreless draw but were defeated 1–0 at Santos Laguna when Jorge Iván Estrada scored in the third minute of second half added time.