The Betway Premiership side secured their place in the continental competition after finishing in third place in the South African top-flight last season.
They made it to the knockout rounds after ending in second place in Group B behind leaders RSB Berkane and ahead of Lunda Sul and Stade Malien.
Zamalek, meanwhile, are the current Confederation Cup winners, following their final win over RS Berkane last season. They once again secured their place in this competition with a third place finish in the Egyptian Premier League last term.
They emerged from Group D as winners ahead of Al Masry, Enyimba and Black Bulls.
While the Egyptian side have a wealth of experience in continental competitions and are five-time CAF Champions League winners, this is Stellies' first time playing in Africa, making this game, "one of the biggest games in the club's history".
Stellenbosch coach Steve Barker said in the Sowetan: "Playing on the continent, I think, is a different level.
"To be playing a team such as Zamalek who are the defending champions, who've won the Champions League five times, it becomes a massive game for us. I don't think we'd be wrong in saying that this is one of the biggest games that the club is involved in.”
"Yes, we're privileged to be in this position. But at the same time, I keep wanting to remind everyone that I think we've earned the right to be on the same park as a team as Zamalek," Barker added.
"A lot of people may believe we don't have an opportunity, but our team is built on resilience. It's built on the ability to overcome challenges. And we are looking forward to this challenge."
Zamalek coach Jose Peseiro has warned his side not to underestimate the Cape Winelands club.
He explained: "It's a good team, very good character, very good character. Congratulations for the coach. They fight, they fight, they fight.
"I think Stellenbosch is one team that has grown up a lot in the last years; showed good quality, good organisation, good capacity, good coach, good players. They show good character on the pitch, character of the fighter. Sure they believe they can go all the way, like us."
Stellenbosch FC moved up to third in the Betway Premiership standings after Sanele Barns scored the only goal in a 1-0 victory against Amazulu at the Danie Craven Stadium on Tuesday.
Stellenbosch coach Steve Barker is eyeing an important three points against AmaZulu in the Betway Premiership on Tuesday.
AmaZulu FC head coach Arthur Zwane believes it's up to the team to qualify for the CAF Confederation Cup next season.
Stellenbosch coach Steve Barker says keeping a clean sheet in the first leg of their CAF Confederation Cup quarter-final clash against Zamalek was crucial in helping the team qualify for the semi-finals of the tournament.
