The Whites enjoyed a clean sweep over their Cairo rivals throughout the past five seasons, winning every game including the cup final in 2008.
After impressively seeing off Petrojet, Hossam Hassan's team also seem to be on a better form than ENPPI, who were downed by Ismaili.
Zamalek will be relying on hotshot Shikabala, who penned a contract extension this week to end speculation about his future.
The flamboyant playmaker scored a terrific goal against Petrojet and should be the man to watch, along with in-form striker Amr Zaki.
Hassan is expected to name an unchanged side, even so he would keep everyone guessing who will be in goal, amid the fierce rivalry between Egypt duo Essam Al-Hadari and Abdul-Wahed Al-Sayed.
Zamalek will be without full-back Ahmed Ghanem due to injury, but midfielder Hassan Mostafa returns to the squad after missing the first two games.
On the other hand, ENPPI hitman Ahmed Raouf is still missing with an ankle problem as the in-form Ahmed Abdul-Zaher is set to deputize upfront.
Ismaili eye top spot
In Ismailia, the Dervishes aim to maintain their perfect form in the league so far by wrapping up another victory over their hosts Gouna.
"I hope we can beat Gouna because last season we drew and lost against them. But this time we are not willing to drop too many points in our quest for the title," said Ismaili assistant manager Ashraf Khedr.
Mark Wotte's men enter their third league game with their thoughts on next week though, when they visit Nigeria's Heartland in a must-win Champions League tie.
Ismaili will be without Abdullah Al-Shahhat who was sent off against ENPPI, while Moroccan international Abdessalam Benjelloun is tipped to start.
Elsewhere, four teams will be looking for their first win as Harras Hodoud host bottom club Arab Contractors, while Smouha visit point-less Petrojet.
Cup champions Hodoud will be without star man Ahmed Eid, who is suspended for four matches following his rant against the referee in last week's draw at Smouha.