Patrice Carteron rolled out the big guns in Mostafa Mohamed and Tarek Hamed in pursuit to revive their quest to qualify for the quarter-finals.
The reserve fixture in this group towards the end of last year finished all square at the Levy Mwanawasa Stadium in Ndola, with Zesco yet to earn a win.
The White Knights made their intentions clear as early as the fifth minute when Achraf Bencharki headed home a cross from Mohammed Onajem with the opponents caught napping.
Zamalek began their group stage campaign with a dismal 3-0 loss away to TP Mazembe, which marked the end of Milutin 'Micho' Sredojevic, but have since regained momentum.
A slow end to the first half continued gathering pace straight in the second, as the White Knights introduced Ahmed Zizou for Joseph Obama as their first change 63 minutes in.
Zesco, whose best finish remains the 2016 semi-final appearance, responded with their first substitution a little later in Umaru Kasumba who came on for Quadri Aladeokun.
However, Zamalek made the points safe right at the death when a delivery from Bencharki found Mohamed who needed no second invitation to take his side to second in Group A.