Leaders America have only won one of their past four matches in the Mexican top tier but a victory at Toluca will see them seeded first in the Apertura's 'Liguilla', meaning they would face the eighth-placed team in the quarter-finals.
Jose Cardozo's Toluca trail America by two points heading into the penultimate round before the play-offs but will be banking on their strong record at home against the Mexico City club.
Toluca have lost just one time in their past 12 home matches against America and come into the game on the back of a 1-0 victory at Tijuana.
America drew 0-0 with Guadalajara in El Super Clasico last week, following on from a 3-2 defeat at Queretaro.
Striker Oribe Peralta, who joined from Santos Laguna before the start of the season, has conceded he has yet to hit his straps with America but pledged to keep working as the finals approach.
Peralta has scored just five goals in 15 matches, well down on the Mexico international's hauls of nine and eight in the Apertura and Clausura last term.
"Missing a lot - more to give," Peralta said.
"It was not the season I expected and I had goals I had set.
"But every game is different, so I am quiet and working."
If America (30 points) win at the Estadio Nemesio Diez, they will secure top spot ahead of Toluca (28) but a draw or a loss will give the latter at least a sniff, while Tigres UANL and Atlas (both 27) would also remain in the hunt if they won their respective matches against Guadalajara and Tijuana.
Atlas dropped to fourth on goal difference after their 4-0 thumping at the hands of Leon last week but will look to bounce back when they host 13th-placed Tijuana, while Tigres are on an eight-game unbeaten run in Liga MX ahead of their trip to Guadalajara, who are 17th.
Queretaro will begin the week's action on Friday when they host bottom club Morelia, who could leapfrog Guadalajara with a win, while Santos Laguna face Pachuca.
Leon have won their past four matches and will look to make it five victories on the bounce when they take on Puebla on Saturday, while Chiapas travel to Monterrey, Veracruz host Universidad Guadalajara and Cruz Azul face up to Pumas UNAM.
