The Cairo giants went two up after ten minutes, thanks to goals from Amr Al-Safti and in-form winger Shikabala, who had a hand in almost every single opportunity for Zamalek.
Midfielder Mohamed Ibrahim, who established himself as a regular first-team player after a series of fine displays, ensured the victory in the 26th minute.
Zamalek will likely have an easy task in the second leg when they face Interclube in Luanda in two weeks' time.
The men in white haven't reached the Champions League group stage since 2005, when they were eliminated from semis at the hands of arch-rivals Ahli.
The hosts needed just four minutes to break Interclube resistance and set the tone for the match's flow.
Al-Safti got ahead of the keeper to head home Shikabala's right-wing free kick from close range.
Interclube had a half-chance through Eduardo Pedro few minutes later when the player's header went across the six-yard box.
Shikabala, one of the main driving forces behind Zamalek's recent revival, doubled the lead after ten minutes.
He superbly controlled Mohamed Abdullah's cross inside the area before hitting a low left-footed shot into the bottom corner.
Ibrahim almost added a third in the 20th minute when his deflected shot went just wide of the post.
He made amends six minutes later when he caught Interclube defenders napping to meet Shikabala's low cross from the left with a neat finish into the net.
Sherif Ashraf should have further extended the advantage on a couple of occasions shortly before the break.
Another pinpoint cross from Shikabala evaded the keeper and went into the path of Ashraf, who fired astonishingly wide with the goal at his mercy.
The former Ahli youngster could have atoned for his mistake few seconds later when he went one-on-one with the keeper but his low shot struck the post.
Zaki Introduction
Dutch coach Ruud Krol introduced striker Amr Zaki in the second half instead of the wasteful Ashraf.
Zaki's campaign with Zamalek this season has been hampered by repeated injuries and some off-field problems.
He combined well with Gamal Hamza more than once but his finishing touch was apparently affected by lack of playing time.
The Egypt frontman almost added a fourth just before the end when he was released by a through pass from Hamza.
Zaki successfully rounded the keeper but couldn't control the ball afterwards as it slipped towards the byline.