Nestor Calderon opened the scoring for the Red Devils on the stroke of halftime when he beat Yosgart Gutierrez with a shot from outside the area.
Chilean Hector Mancilla added the second in the 58th minute with his eighth goal of the competition, making him joint top scorer with his compatriot Humberto Suazo of Monterrey.
Luis Angel Landin pulled one back for the Blue Machine one minute later but Edgar Duenas added Toluca's third in the 76th minute after running onto Antonio Naelson's pass and placing his shot past Gutierrez from the edge of the area.
Toluca, unbeaten after 11 games, top Group Three with 23 points while Cruz Azul are bottom of Group Two with 11.
America and Pumas UNAM disappointed a 70,000 crowd at the Azteca by drawing their derby 0-0, a result which kept Pumas top of Group Two.
Guadalajara, Mexico's most popular club, dropped to fifth in Group Two with 12 points after losing 1-0 at Tigres UANL, who ended a five-match winless run.
Tigres, under Argentina's 2006 World Cup coach Jose Pekerman, stayed fifth in Group Three with 10 points after Paraguay defender Pedro Benitez scored in the 39th minute.
Argentine Christian Gimenez scored a hat-trick to give Group One leaders Pachuca a 3-0 win over Necaxa and keep them on course for a quarter-final place.
The 18 teams meet each other once in the qualifying stage but are divided into three groups.
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