The Cairo giants, who have not won Africa's blue-riband competition since 2002, meet Tusker in the first leg of the second preliminary round at the Nyayo National Stadium in Kenyan capital Nairobi.
Zamalek twice lost in the final in 2016 and 2020 but are hoping they can make it happen this time around, even though they will have to play with a similar squad to the one that suffered a surprise group-stage exit last season.
The club were banned from registering any players for two transfer windows after striking a new deal with youngster Hossam Ashraf while he had already signed for a Cameroonian academy.
They were given a reprieve though after learning that they can register those who were away on loans last season, including in-form winger Mostafa Fathi and Moroccan Mohamed Ounajem.
But both will not be eligible for Zamalek's two games against Tusker as they could be only registered in the team's African roster in January.
"We are taking it one step at a time in the African Champions League," French coach Patrice Carteron, who led Zamalek to their first Egyptian Premier League title since 2015 last season, told reporters.
"We are looking to get a positive result in the away game and then qualify for the group stage as a first step. We are not thinking beyond that now.
"We highly respect our opponents, a strong team that has recently won the domestic Super Cup. But we will be only looking for a win."
The second leg takes place in Alexandria next Friday.
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