Colombians Teofilo Gutierrez and Luis Perea gave the Blue Machine a 2-0 half-time lead and Argentine striker Mariano Pavone's second half hat-trick completed the rout as the team earned a fifth consecutive victory.
Former Argentina winger Cesar Delgado pulled one back for Monterrey, who squeezed into the knockout phase of the Clausura championship.
The top eight in the 17-match league phase qualified for the quarter-finals with Cruz Azul going through in fifth place.
UANL Tigres, America, Atlas, Morelia, Santos Laguna and UNAM Pumas have also qualified.
Monterrey finished ninth but eighth-placed Queretaro were relegated with the first division's lowest points average over three seasons and so cannot take part in the play-offs.
The top-of-the-table clash at the Azteca ended with Tigres beating hosts America 2-0 to finish as leaders of the league phase and they will meet Monterrey in the two-legged quarter-finals.
Tigres' Argentine striker Emanuel Villa is happy to be facing Monterrey in the last eight, hoping his team can avenge their defeat by the same rivals last weekend.
"I would welcome it, we knew it was a possibility. We played only a week ago and it didn't go well for us but that's what's nice about football, it soon gives you a chance for revenge," Villa said.
"From the start of the championship, we set out to be a competitive team and we've done that, getting a good place in the regular (league) phase, but now we've got the hardest part," he said.
Record 11 times champions Guadalajara crashed to their sixth consecutive defeat, 4-0 at Apertura winners Tijuana.
Both sides finished outside the play-offs, Tijuana because they have prioritised the South American Libertadores Cup where they have reached the last 16 and Chivas due to their dismal form.
"It's frustrating, really, knowing we'd done good work at first, going nine matches unbeaten, only to fall into complacency and then we were unable to pick ourselves up again," Chivas coach Benjamin Galindo said.
"These defeats are what hurts most, because of the manner. You have to defend this shirt with honour, you can win, lose or draw, but you must always have that pride for the club you're at," he told Guadalajara's website.
"We're ashamed (but) we're planning to build a good team so the fans believe in us again ... We must make several changes to have a competitive team," he added.