Veteran Shikabala started from the bench for the hosts, who lined-up with Mostafa Mohamed and Achraf Bencharki upfront. Meanwhile, Abdelraouf Benguit and Ibrahim Ouattara started up top for the visitors.
The Tunisians stunned the home crowd after Benguit ran onto a through-ball just outside the area from Hamdou Elhouni to slot into an empty net following the 27th minute.
Zamalek levelled four minutes later as a stunning 30-yard strike from Mohamed Onajem caught Moez Ben Cherifa off guard before bursting the net.
Bencharki, who starred in their recent CAF Super Cup triumph over Esperance, got a clear chance to put his side ahead after 35 minutes but headed wide while Mahmoud Alaa cracked the top of the woodwork with a first-time effort for minutes later.
No changes came from either side following halftime, as the North African duo looked for a decent first-leg outcome.
Esperance, who ended the first spell on a high, went close to regaining the lead with a smart shot from Benguit but Mohamed Abou Gabal palmed for a corner with 52 minutes played.
The defending champions installed more firepower ten minutes later with Abderrahmane Meziane filling in for Mohamed Ali Ben Hammouda.
Zamalek went ahead after a cross into the area on 72 minutes found Bencharki who volleyed into the far corner from the right side.
Tampers soon boiled over as Mohamed Ali Ben Romdhane receieved his marching orders following a studs-up challenge within a minute.
The White Knights round up the contest in stoppage time after Alaa fired home from the spot following a foul in the area, giving the Egyptians a first-leg advantage.