League leaders Cruz Azul will travel to fourth-placed America, while Toluca - who sit second - face one of the toughest trips in Mexican football as the trek north to Tijuana's Estadio Caliente.
Those fixtures could see all three of Cruz Azul, Toluca and America drop points in round 14, providing Santos Laguna with the opportunity to gain ground on their rivals for the Clausura championship.
Pedro Caixinha's Santos Laguna have not lost in four Liga MX games, while their unbeaten run stretches to seven in all competitions.
That should give them plenty of confidence as they head east to local rivals Monterrey, despite the home side having experienced some resurgence over the past fortnight.
Monterrey have won their past two matches, winning 2-1 at Pumas UNAM before a 3-2 triumph over Atlante.
But with Mexico international Oribe Peralta in fine goal-scoring touch, Santos Laguna should be too strong for their hosts.
Peralta has scored four goals in his side's past four league games to move to 16 across both the Apertura and Clausura seasons.
If Santos Laguna win in Monterrey they will rise to 23 points, which could take them within six of leaders Cruz Azul and five of second-placed Toluca.
America and Pachuca will also start the round on 20 points ahead of their games against Cruz Azul and Guadalajara respectively.
Cruz Azul will take on America after their CONCACAF Champions League semi-final first leg against Tijuana, while Toluca also have continental commitments before they visit the Estadio Caliente with a trip to Costa Rica to play Alajuelense.
Tijuana's home record is formidable - just one defeat in all competitions in 21 games - and will give Toluca something to worry about on Friday.
Pachuca will have to be wary of Guadalajara, who will be desperate to bounce back after losing 4-0 to arch-rivals America last week.
Morelia will host Veracruz in the other game on Friday, while Leon face Queretaro and in-form Atlas will entertain Puebla on Saturday.
The round will finish on Sunday with Chiapas heading to Pumas UNAM, while Atlante clash with Tigres UANL.
