Valencia struck twice after Eduardo Vargas opened the scoring for the hosts in the first leg of the semifinal tie.
The result leaves Tigres in a strong position to reach a third final in the past four editions of the competition heading into the second leg on April 10.
They needed just eight minutes to open the scoring, Vargas tapping in after Santos Laguna goalkeeper Jonathan Orozco could only parry a Julian Quinones strike.
Santos had a couple of decent chances before Valencia doubled the home side's lead in the 27th minute.
The former West Ham and Everton forward got on the end of a Luis Rodriguez cross to head in his side's second.
Just 10 minutes later it was 3-0, Valencia putting away a cross from the right from Luis Quinones.
While the scoring would stop there, the victory leaves Tigres in a commanding position heading into the second leg, though Santos Laguna is a club that has shown well at home in the competition.
Santos posted a 5-0 win over Marathon at home in the round of 16 before being pushed in a 4-2 win over the New York Red Bulls in the second leg of their quarterfinal tie.
And while that might lead to some measure of confidence heading into the match, Tigres' record in the competition so far will not.
While the club has been much more dominant in home matches, no club has managed to score more than one goal on Tigres in any single match so far in the competition, and only Saprissa could better them, taking a 1-0 win in the first leg of their last-16 tie before falling 5-1 in the second leg.
The winner of the semifinal will take on either Sporting Kansas City or Monterrey in the final, with those two clubs set to face off in the first leg of their semifinal tie on Thursday in Mexico, while SKC will host the second leg on April 11.