Mexico played a man up after Paraguay goalkeeper Aldo Bobadilla was ejected in the third minute and went on to a 6-0 rout in the Copa America, setting up a semifinal against tournament favorite Argentina.
Argentina, which beat Peru 4-0 in Sunday's second quarterfinal, knocked Mexico out of last year's World Cup in the second round, coming from behind for a 2-1 overtime victory in Leipzig, Germany.
Their semifinal in the South American championship will be on Wednesday in Puerto Ordaz. Defending champion Brazil meets Uruguay in Tuesday's semifinal at Maracaibo. The final is on Sunday.
Paraguay was disoriented moments into the quarterfinal at Maturin when Bobadilla tripped up Nery Castillo and was sent off.
Third-string 'keeper Joel Zayas came in for midfielder Jonathan Santana, upsetting Paraguay's attack, and Zayas never touched Castillo's penalty shot.
"We committed the mistake of unraveling very quickly," Paraguay coach Gerardo Martino said. "We're going home totally humiliated and emotionally quite poor."
Gerardo Torrado doubled Mexico's lead in the 22nd minute, and Castillo scored his second in the 38th to bolster his tournament tally to four, two shy of leader Robinho of Brazil.
Fernando Arce, Cuauhtemoc Blanco and Omar Bravo scored in the second half to cap the blowout.
Mexico has reached the semifinals for the fifth time in seven appearances as a guest.