The Chivas, who scored through midfielders Antonio Gallardo and Marco Fabian de la Mora, and striker Erick Torres, took their goals tally to eight in two matches, while America had Brazilian Rosinei sent off with half an hour to go.
Mexico's most popular team lead with 25 points from 14 matches, two points ahead of Santos Laguna, who have a game in hand, and Chiapas with three matches to go. The top eight qualify for the knockout phase.
Gallardo headed Guadalajara in from after six minutes from a left cross by De la Mora, who scored a hat-trick in the 5-2 win over Estudiantes UAG last weekend.
America, with 14 points and in danger of missing the quarter-final cut, equalised six minutes later through Ecuador's Christian Benitez, who headed home Argentine playmaker Daniel Montenegro's cross.
De la Mora restored Guadalajara's lead within five minutes when he tapped home from inside the six-yard box after goalkeeper Armando Navarrete spilt a corner.
A minute later, Torres, who goaled twice last weekend, completed the scoring with a header in an action-packed opening 18 minutes.
Uruguayan Ivan Alonso hit a hat-trick in half an hour for Toluca in their 4-3 home win over Puebla to go top of the scorers' chart with 10 goals.
Former Colombia goalkeeper Miguel Calero, who was capped 50 times, retired at the age of 40 at the end of his club Pachuca's 0-0 draw at home to title holders Pumas UNAM on Saturday.
