Diego Rossi's two second-half goals propelled the Columbus Crew past defending champions Inter Miami 3-2, securing their spot in the Leagues Cup quarter-finals.
The Uruguayan forward lifted the host Crew level in the 69th minute and netted the decider in the 80th to dethrone Miami, this season's overall MLS season leader.
Miami star Lionel Messi did not play, as he was still sidelined with a right ankle injury suffered a month ago in Argentina's Copa America final win over Colombia.
With the victory, the Crew will play host to a Saturday quarter-final against New York City, who won 2-1 over Tigres.
Paraguayan midfielder Matias Rojas gave Inter Miami a 1-0 lead in the 10th minute and compatriot Diego Gomez doubled the margin with a goal in the 62nd before US striker Christian Ramirez answered for the Crew in the 67th, setting the stage for Rossi's winning brace.
The tournament features MLS and Liga MX Mexican sides, with Messi leading Miami to last year's inaugural crown shortly after arriving in Florida.
New York City rallied to reach the last eight.
Argentine midfielder Guido Pizarro, the Tigres captain, opened the scoring with a header in the 18th minute but New York City netted the equalizer in the 20th through another Argentine midfielder, Maxi Moralez.
Uruguayan Santiago Rodriguez scored the final goal in the 65th minute from the left side on a left-footed shot inside the far post to give NYCFC the victory.
In Cincinnati, Tai Baribo's two goals lifted the Philadelphia Union to a 4-2 triumph over the hosts.
Philadelphia grabbed a 2-0 lead on goals by Danish forward Mikael Uhre in the 51st minute and Israeli striker Baribo in the 61st.
Czech midfielder Pavel Bucha answered for Cincinnati in the 66th minute and US defender DeAndre Yedlin netted an equalizer for the hosts in the 80th minute.
The Union responded on goals by Baribo in the 82nd and US substitute Quinn Sullivan in the 84th.
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Mazatlan advancesNext up for Philadelphia will be a home quarter-final on Saturday against Mazatlan, which defeated Cruz Azul on penalties after playing to a 2-2 draw in Washington.
Mazatlan grabbed a 2-0 half-time lead on goals by Bryan Colula in the 40th minute and Panamanian midfielder Edgar Barcenas in the first minute of stoppage time.
Cruz Azul fell to 10 men in the fourth minute of the second half when Argentine defender Gonzalo Piovi was shown a red card.
Cruz Azul, however, was far from done as Uriel Antuna scored in the 84th minute and Colombia defender Willer Ditta added an equalizer in the opening seconds of stoppage time.
In penalties, Antuna, Ditta and Giorgos Giakoumakis failed to convert and Mazatlan won 3-1 to advance.
In later quarter-finals on Tuesday, Toluca was at Colorado with the winner set to face Mexican champions Club America or St. Louis in the quarter-finals.
San Jose was also at Los Angeles FC with the winner set to visit Seattle on Saturday.
All-time French goals leader Olivier Giroud is available for LAFC for the first time since the 37-year-old striker's move from AC Milan in May.
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