The Mexicans did all the hard work in the first half with Jair Pereira firing in the opener on 32 minutes.
Goals in the shadows of half-time from Mariano Pavone and Gerardo Torrado sealed the victory for Cruz Azul.
Mexican side Toluca got their second win in as many games in Group 6 as they outlasted Guatemala's Comunicaciones 2-1 after an early flurry of goals.
Toluca secured an early lead as Raul Nava fired in the first on 17 minutes before the Guatemalans struck back through Minor Lopez two minutes later.
The winner was scored from the penalty spot by Juan Cacho in the 27th minute as Toluca held on for victory with their job made easier by the sending off of Comunicaciones defender Jose Contreras in the second half.
Panama's Sporting San Miguelito managed to overcome Costa Rica's Alajuelense 1-0 at the Estadio Rommel.
John Pretelt scored the only goal of the contest as San Miguelito avenged their loss to Club America in their first Group 4 match.
