Zamalek were given a dream start inside two minutes when Youssef Obama turned home a ball from Mohamed Abdel-Shafy for the game's opening goal.
The Tunisian side struggled to get a look in following the opening exchanges, as Moustafa Mohamed went close to doubling the Egyptian side's lead with a half-volley 16 minutes gone.
Mohamed was in the thick of things again after the 25th minute with a rasping curling attempt flying narrowly over the top of Mo'az Ben Sherifa's goal.
The White Knights threatened again five minutes to halftime as Zizo's close-range attempt needed a goal-line clearance from the Champions League winners.
After playing second fiddle the whole of the first half, Esperance started the second period with renewed energy with no changes off the bench from either side.
As a result, Abdelraouf Benguit brought the Tunisians level from the penalty spot on 54 minutes after the Video Assistant Referee penalised the Egyptians for a handball in the 18 yard area.
Zamalek, however, quickly reclaimed the lead through Achraf Bencharki three minutes later with a stunning top-drawer finish.
Mooine Chaabani's outfit probed and probed for a way back in the final stages, whilst the Egyptians looked to hang onto their lead.
Bencharki completed his brace in time added on with another decent finish to hand Zamalek their fourth Super Cup title and first since 2003.