It was the Egyptian side's first win in Group A and moved them back into contention with two games remaining.
Ahmed Eid opened the scoring in El-Gouna with a sixth-minute penalty only for Lennox Bacela to equalise for Orlando just after the half hour.
Salah Soliman won the game six minutes into the second half to move Zamalek to within three points of their opponents.
Current CAF Champions League holders Al Ahly moved level on points with Orlando at the top of group A with a 2-1 victory over Leopards de Dolisie.
Abdallah El Said and Waleed Soliman put the seven-time winners two goals ahead, and although Sidoine Beaullia grabbed a consolation for the Congolese champions Al Ahly were able to hold onto their second win of the group.
In group B, ES Tunis moved two points clear of Cotonsport with a 1-0 victory over Ivorian champions Sewe Sport.
Anthar Yahia scored the only goal of the game just before the hour to give the Tunisian side their third consecutive win.
Recreativo do Libolo were denied a second win of the group as Moussa Yedan earned Cotonsport a 1-1 draw in Calulo.
Yedan struck in the 32nd minute to cancel out Aguinaldo's opener eight minutes earlier.
Cotonsport maintained their three-point advantage of the Angolan side with the draw, and kept alive their hopes of qualifying for the semi-finals.
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