Arta Solar scored the two goals in the 55th and 60th minute, securing the very first-ever victory for a Djiboutian side over an Egyptian team.
The game was played at Azam Complex Stadium in Tanzania due to CAF's decision not to register Arta Solar Stadium in Djibouti.
Zamalek, winners of the Confederation Cup title in 2019, played without several key players, including Ahmed 'Zizo' Sayed and Ahmed Fatouh, who were sidelined with injuries.
The White Knights maintained the upper hand in the first half but Shikabala and Seifeddine Jaziri missed several easy scoring chances.
A very organized Djiboutian side dominated the second half and scored two goals.
Arta Solar striker Gabriel Dadzie opened the scoring for the hosts in the 55th minute.
Substitute Doualeh Mahamoud Elabeh then doubled the lead just five minutes later
Substitute Mohamed Fouad missed an easy scoring opportunity eight minutes before the final whistle.
The 38-year-old former Chelsea and Lille player Salomon Kalou featured in Arta Solar squad on Saturday.
Kalou, a former UEFA Champions League winner with Chelsea in 2012, made 15 appearances for Arta Solar since joining in 2022, scoring ten goals.
Zamalek now face an uphill battle to reach the round of 16 in the second leg in Cairo on 1 October.
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