Santos, the overall leader in the Mexican regular season, faces an uphill battle in its bid to make the Torneo Apertura final after being thrashed by UNAM, 3-0, in Thursday's semifinal first leg in Mexico City.
Argentine Ignacio Scocco scored twice and Mexican Hector Moreno had the third goal for Pumas. American Edgar Castillo started for Santos, which must win Sunday's second leg by three goals to advance to next week's final.
Guadalajara takes a 1-0 lead over Atlante into Saturday's second leg of the other series in Cancun. Ramon Morales' penalty kick gave Chivas the win in the first leg.
Castillo had scored his first goal for Santos in the first-leg quarterfinal win over Morelia.