Bruce Arena's men head south, trying to overcome a massive challenge from the Liga MX side and advance to the semifinal.
Brazilian striker Samuel scored the only goal of the quarterfinal first leg, which ended in a 1-0 Galaxy victory at the StubHub Center last Wednesday.
The MLS side will face a big challenge at the Estadio Caliente, where Xolos are unbeaten in 18 of their last 19 league games. They also went unbeaten at home during Copa Libertadores and CCL group play.
A reserve-heavy Club Tijuana lost 2-1 to Cruz Azul in league play on Saturday, while the Galaxy were given the weekend off after MLS moved a scheduled match against D.C. United to later in the season.
Last season, the Galaxy fell in the semifinal to eventual champion Monterrey. Tijuana, meanwhile, is making its first appearance in the continental competition.
The winner of the quarterfinal will face the winner of Sporting Kansas City - Cruz Azul. The defending MLS champion has a 1-0 lead heading into Wednesday's second leg in Mexico City.
Midfielder Fernando Arce trained with Tijuana on Monday evening after missing the first leg with injury but is still not expected to start. The Galaxy have no major injury concerns. No players are suspended.