An early Mostafa Mohamed goal set up Zamalek to defeat Ismaily 3-1 in Cairo to clinch second place in the Egyptian Premier League and secure qualification for the 2021 CAF Champions League.
Had the White Knight not collected three points, they could have been overtaken by 2020 CAF Confederation Cup runners-up Pyramids and lost out on a place in the elite African club competition.
Champions Al Ahly will be the other Egyptian representatives in the Champions League with Pyramids and fourth-place Al Mokawloon Al Arab entering the CAF Confederation Cup.
Zamalek swiftly stamped their authority over mid-table Ismaily as Mohamed and Democratic Republic of Congo-born Kabongo Kasongo scored within 24 minutes.
Moroccan Achraf Bencharki stretched the lead to three goals during the second half before Wagih Abdelhakim reduced arrears after goalkeeper Mohamed Abougabal blundered.
Zamalek now switch their attention to the 2020 Champions League as they will defend a 1-0 lead over Raja Casablanca of Morocco this Sunday in the second leg of a semi-final in Cairo.