Cruz Azul, the best team all season in Mexico, was knocked out of the quarterfinals Saturday with a 2-0 loss to UNAM Pumas.
Pumas advanced 3-2 on aggregate after losing 2-1 in the first leg earlier in the week.
Martin Bravo and Juan Carlos Cacho scored the goals in Pumas' best match of the Apertura season.
In Saturday's other second-leg quarterfinal match, America defeated San Luis 4-1 to advance. The first leg was scoreless.
On Sunday, Monterrey faces Pachuca and Santos play Jaguares. Both of those quarterfinals are 1-1 after the first leg.
It was a bitter exit for Cruz Azul, which was trying to win its first league title since 1997. Cruz finished the regular season with 39 points from 17 matches, 17 more points than Pumas.
The bad day for Cruz got worse when midfielder Gerardo Torrado left in the 27th with an injury, and in the 42nd Cruz went down to 10 men after Horacio Cervantes was sent off for a hard tackle.
In America's victory at Aztec stadium in Mexico City, Vicente Sanchez of Uruguay scored in the 15th, and America went ahead 2-0 on an own-goal by Anibal Matellan. Enrique Esqueda and Matias Vuoso sealed the scoring for America.
America, which had lost in the quarterfinals the past two seasons, reached the semifinals for the first time since 2007 when it eventually lost the final to Pachuca.