Toluca, who finished top of the league standings and qualified in first place for the eight-team knockout phase, went through to the semi-finals 5-2 on aggregate after Thursday's 2-1 win in the first leg at Guadalajara's Omnilife stadium.
Two goals in three minutes inspired by Brazilian-born Mexico international Antonio Naelson Sinha and scored by fellow Brazilian midfielders at the Nemesio Diez ground in Toluca sealed the Chivas' fate.
Sinha took a quick free-kick in the 56th minute while Guadalajara were lining up their wall and Paraguay's Edgar Benitez then passed to holding midfielder Wilson Thiago who opened the scoring.
Two minutes later, Lucas Silva made the best of a mistake by visiting goalkeeper Luis Michel to head the second goal and virtually put the tie beyond Dutch coach John van't Schip's team.
Substitute Juan Carlos Cacho scored a third goal for the Red Devils from Silva's left cross in a counter-attack in the 72nd and striker Erick Torres pulled one back 10 minutes later.
Guadalajara's arch-rivals America, looking for their 11th league title, lost 2-1 at home to Morelia at the Azteca in Mexico City on Saturday but went through 3-2 on aggregate.
"We had a wake-up call today," Eagles coach Miguel Herrera said.
"Fortunately we already held a lead, but we lacked concentration in the first half and they took advantage. Luckily Raul Jimenez scored a good goal that gave us this opportunity to go through."
Promoted Leon upset Cruz Azul 3-0 with two first-half goals from Uruguayan striker Matias Britos to qualify 4-2 on aggregate having lost 2-1 away in Wednesday's first leg.
Luis Delgado scored a late third goal for Leon after Cruz Azul's Argentina former River Plate and Lanus striker Mariano Pavone had been sent off with 10 minutes remaining.
Cruz Azul, Mexico's fourth most successful club with eight titles after Guadalajara (11), America and Toluca (both 10), have gone 15 years without winning the championship.
Border-town team Tijuana were favourites to complete the semi-final line-up defending a 1-0 lead at home to Monterrey in the second leg of their quarter-final later on Sunday.
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