The Egyptian giants sit bottom of Group A after four matches, and know a victory over pool leaders V.Club is required in Cairo on Sunday.
However, their preparations have been affected by upheaval and disarray, as they go into the clash with a new coach - Hossam Hass, who replaced Mido last week - and with the club's fans at odds with those in the boardroom.
A group of Zamalek fans stormed the club's headquarters and vandalised chairman Mortada Mansour's office on Saturday after he had publicly criticised their attitude.
Despite this unsavoury incident, new coach Hossam remains upbeat of turning things around on the pitch and guiding Zamalek to their first Champions League last-four tie since 2002.
"We will fight until the last minute to reach a semi-final," he said.
"The team will have a different style, especially with the recent new signings that will add a lot to our performance."
In Group A's other fixture, Congolese side TP Mazembe face another club who recently parted ways with their coach.
Al-Hilal of Sudan fired Paulo Campos for his aggressive behaviour towards match officials during their 2-1 away defeat to AS Vita Club in the last round of the competition.
The former coach's assistant Al-Tag Mahgoub will be in charge this weekend, knowing that anything but a win will see his side virtually eliminated from the competition with one match left to play.
Meanwhile, in Group B, the only undefeated team left in the competition, ES Setif of Algeria, take on bottom-placed Esperance on Saturday safe in the knowledge that three points will seal their semi-final place.
And a similar scenario beckons for CS Sfaxien when they take on Al Ahli Benghazi on Friday, as a draw will guarantee their progression.