Pumas took advantage of Club America's ill discipline to win 3-0 in Thursday's Liga MX Apertura semifinal first leg.
Ismael Sosa, Gerardo Alcoba and Eduardo Herrera scored second-half goals in the Mexico City derby inside Estadio Azteca, with America ending the game with only nine players.
With Pumas finishing ahead of America in the regular season, Las Aguilas will have to score at least four goals in Sunday's second leg to have any chance of reaching the final.
America had dominated the first half and piled pressure on the Pumas defense. That continued until America's Paraguayan center-back Pablo Aguilar was sent off for a late tackle on Sosa in the 52nd minute.
Sosa latched onto a Fidel Martinez cross to capitalize and score a vital away goal in the 62nd, before Miguel Samudio pushed Sosa over and received his second yellow card two minutes later.
America continued to push forward and was caught on the counter when Alcoba swept in a loose ball inside the penalty area in the 74th, with Herrera heading in to virtually seal the series in the 78th.
The victory will go down as a famous one for Pumas against their main rival America, who will represent Mexico in Japan at the Club World Cup.
Tigres and Toluca ended their semifinal first leg in Estadio Universitario deadlocked at 0-0, largely thanks to Toluca goalkeeper Alfredo Talavera.
Talavera saved a fiercely struck Juninho penalty in first-half injury time to keep the clean sheet and send his team into Sunday's second leg level.
Tigres enjoyed the vast bulk of possession (70 percent) and 18 shots to Toluca's four, but couldn't break down the away side.
France international striker Andre-Pierre Gignac hit the crossbar with a header in the 27th minute and had another couple of half-chances in the first 45, but Tigres failed to turn the possession into dangerous goalscoring opportunities.
Antonio Rios fouled Javier Aquino in the penalty area just before halftime and when it appeared Tigres would take the lead, Talavera produced a memorable save from the well-hit penalty.
Tigres seemed to run out of ideas in the second half and Christian Cueva went close in the 61st, from one of Toluca's rare attacks.
The winner of Sunday's second leg in Estadio Nemesio Diez will face America or, most likely, Pumas in the Apertura final.