The White Knights now have 16 points from seven matches, two ahead of second-placed Masry who defeated Ghazl El-Mahalla 2-1 on Wednesday.
Veteran midfielder Abdallah El-Said opened the scoring in the seventh minute, converting a penalty after sending the Ismaily goalkeeper the wrong way.
Brazilian winger Juan Alvina, who won the penalty, had a chance to double the lead in the first half.
In the 27th minute, he missed an open goal, and moments before the break, his effort struck the post.
Palestinian striker Oday Dabbagh also spurned a clear opportunity in the 45th minute, sending a close-range shot over the bar with the goal at his mercy.
Zamalek were forced to make a first-half substitution when right-back Omar Gaber suffered an ankle injury.
With no available right-back on the bench, Moroccan defender Sallah Moussaddaq filled in for the remainder of the game.
Ismaily struggled to offer any real challenge to the visitors, with the lack of experience from their youthful squad raising further doubts about their prospects in the league.
In the second half, Zamalek sealed the win with a second goal.
Dabbagh, redeeming himself for his earlier miss, finished coolly with a chip four minutes before the hour mark.
The goal gave Zamalek a commanding presence as they controlled the final 30 minutes, with Ismaily failing to mount any serious threat.
The hosts' only chance came in the 80th minute when Abdel-Rahman El-Dah intercepted the ball from Zamalek defender Mohamed Ismail, only for Hossam Abdel-Meguid to clear his shot off the line.
Zamalek will next face Gouna at Cairo Stadium on Tuesday.
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