Ittihad's helpless keeper Al-Hani Soliman was given a torrid time by Shikabala, who ignored doubts over his commitment to the Egyptian national team to produce a dazzling display at Cairo Stadium.
Towering striker Ahmed Gaafar was also on the scoresheet for Zamalek, who fell behind to an early Ittihad goal before twice surviving a brave fight back from the struggling Alexandria-based club.
Wizard Shikabala, who was also under fire after being videoed insulting Zamalek's arch-rivals Ahli, took his tally to eight goals to overtake ENPPI striker Ahmed Abdul-Zaher as the league's top scorer.
Zamalek, who eye their first league title since 2004, moved seven points clear on top of the table. Second-placed Police Union can narrow the gap if they beat Gouna on Friday.
Ittihad, who suffered their second consecutive defeat under new coach Mohamed Amer, remained second from bottom with nine points from 12 matches.
Shikabala Show
The home fans' enthusiastic cheers were muted by ex-Zamalek striker Hani Al-Egeizi, who needed nine minutes to score against his former club.
Mahmoud Shaker whipped in a cross from the left and Al-Egeizi towered unmarked between two static defenders to head home past Zamalek keeper Abdul-Wahed Al-Sayed.
Zamalek pushed forward to grab the equalizer and their pressure resulted in a 16th-minute penalty after Shikabala was tripped by Shaker.
Spot-kick specialist Mahmoud Fathallah stepped up but his weak low shot was easily saved by Ittihad keeper Al-Hani Soliman.
Zamalek made amends on 33 minutes when Ittihad defender Al-Sayed Farid received a second yellow card for a last-man foul on Gaafar and Shikabala arrowed the ensuing free kick into the top corner of the net.
Gaafar put them in front three minutes later when he gathered a rebound after a mix-up between an Ittihad defender and Soliman to slot into an empty net following a neat exchange of passes between youngsters Omar Gaber and Mohamed Ibrahim.
Zamalek looked to be cruising for a comfortable win but Ittihad were dangerous on the break despite being a man down, with the pace of in-form striker Edet Otobong causing them constant problems.
One of the Cameroonian's trademark surging runs saw him outpace midfielder Ibrahim Salah to collect a punt from Soliman and break clear before chipping the ball over Al-Sayed to level the score on 40 minutes.
Shikabala restored Zamalek's advantage two minutes before the break when his low free kick from the right eluded a host of defenders and surprisingly went past Soliman, whose shaky displays once again cost Ittihad dearly.
Al-Egeizi scored his second of the night in the 56th minute to make the score 3-3 after Al-Sayed failed to deal with his seemingly innocuous free kick from the edge of the area.
Ittihad's joy, however, was cut short by the impressive Shikabala, who curled another free kick over the wall and into the net with 15 minutes remaining to spark wild celebrations in the stands.