Moussa Guindo gave the home side a first-half lead, before substitutes Sinaly Bamba and Antoine N'Gossan completed the rout in the second half.
ASEC jumped from rock bottom to second place in the group with five points, while Zamalek remain with four points in third place.
The Ivorians were in full control of play at Stade Robert Champroux de Marcory, despite having only one goal to their records prior to the game.
The breakthrough came after 25 minutes, courtesy of a fluke by Guindo, whose attempted cross flew over Mohamed Abdul-Monsef into the net.
Shortly after the break, the Whites were unlucky again when Junior Agogo's effort came off the post, in what was arguably the best chance for the visitors.
ASEC's assault was increasingly intensifying in the second half and their efforts paid off in the 68th minute.
Substitute N'Gossan waltzed around Mahmoud Fathallah at the left flank before feeding Bamba with a deft pass, and the latter controlled the ball and notched home the second from close range.
Five minutes later, ASEC were awarded a penalty after Abdul-Monsef fouled an opponent. N'Gossan converted comfortably.
To add to Zamalek woes, skipper Ayman Abdul-Aziz and key defender Wissem El Abdi were both cautioned in the game, which means they won't be available against Ahli next month.