Although Zamalek missed their international players, who are away on African Nations Cup duty, their starting line-up still boasted some regular players, including defender Mohamed Abdel-Ghani, winger Mohamed Ounajem and striker Omar El-Said.
Hesham Adel fired Mahalla in front on 35 minutes with a delightful curling shot from the edge of the area.
Abdo Yehia doubled the lead on the stroke of halftime with a composed finish after Adel played him in before completing the rout with a superb looping header following a free kick five minutes from time.
Zamalek were indebted to goalkeeper Mohamed Awad for denying Mahalla at least a couple of certain goals.
The White Knights are now virtually out of the race to finish on top of C and reach the semis of the inaugural EFA Cup edition, the third-tier domestic competition, as they could only collect one point from three games.
They lie at the bottom of the group, four points behind joint leaders Mahalla and Enppi with only two matches remaining. Zamalek's goal difference of -five also makes their task to advance difficult.
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