Al Ahly promote youth team coach Mabrouk
Youssef, given the top job in 2013, had come under increased pressure after their elimination from the CAF Champions League at the hands of Al Ahli Benghazi in the second round.
And the 43-year-old - who guided the club to the Champions League title last term - parted company with the club on Thursday.
With the group stages of the CAF Confederation Cup due to begin later this month, it will be Mabrouk who takes charge of the team following Youssef's resignation, with Ahram Sports quoting the club website as having accepted his decision.
"Ahly management has accepted the resignation of coach Mohamed Youssef," they quoted the club's official website as saying.
Youssef is not the only person leaving the club with director of football Sayed Abdel-Hafiz and football supervisor Hady Khashaba also resigning.