The Cairo giants fell behind to two goals from playmaker Ayman Hefni, who said before the match he hoped to impress to earn an Egypt call-up, and Ayman Kamal.
They hit back with two goals from Shikabala and substitute Ahmed Gaafar, whose introduction added much-needed firepower to Zamalek, in the last five minutes of the first half.
Hussein Hamdi restored MCDR's advantage nine minutes past the hour mark but Gaafar struck again few minutes later to equalize and stake his claim for a regular place in Zamalek's starting line-up.
Although Gaafar was the team's top scorer last season with nine goals, coach Hossam Hassan opted to put him to the bench and rely on Amr Zaki as a lone striker this term.
A trademark header from central defender Mahmoud Fathallah with seven minutes remaining gave Zamalek all three points as MCDR were punished for the needless attacking approach they had after going in front.
Zamalek's third successive victory puts them second in the league table with 14 points, just one behind leaders and surprise package Police Union.
MCDR, who made a decent start to their league campaign, lie 11th on eight points from seven matches.
Individual Effort
Zamalek's enthusiastic start could have resulted in an early goal but the overlapping Hossam Arafat saw his low shot from inside the area strike the post.
Zaki, who played on his own upfront and was supported by attacking midfielders Arafat, Shikabala and Hussein Yasser, also came close with a header that narrowly missed the target.
However, it was MCDR who grabbed the lead on 14 minutes after a fine individual effort from the skilful Hefni.
The 24-year-old cut inside Mohamed Abdul-Shafi inside the area before hitting a low shot which bounced in front of off-form keeper Essam Al-Hadari before flying into the net.
The Egypt guardian, who made a U-turn on his decision to leave Zamalek in January, was taunted by his own fans who chanted the name of their favorite goalie Abdul-Wahed Al-Sayed.
Al-Hadari, who joined Zamalek from Ismaili in the close season, was also to blame for MCDR's second goal in the 34th minute.
He let a harmless and weak shot from Hamdi elude him and come back off the post before finding the unmarked Kamal, who slotted into an empty net.
Zamalek reduced the arrears in the 41st minute when the combative Zaki held off his challenger with his back to goal before squaring the ball for Shikabala to tap in easily at the far post.
Instant Impact
Gaafar replaced Qatari winger Yasser and made an instant impact as he leveled the score with a looping header after making the most of a mis-hit shot from Arafat and the poor position of MCDR keeper Mostafa Kamal.
Zamalek continued to commit mistakes at the back though and they were punished when Hamdi restored the hosts' advantage in the 69th minute.
An attempted clearance by Zamalek's central defender Hani Saied ballooned over his head and went backwards to find Hamdi, who went through and slotted home with aplomb.
Instead of tightening their defense to preserve their lead, MCDR pushed forward to leaves gaps at the back which Zamalek exposed to emerge winners.
Gaafar came to the White Knights' rescue in the 73rd minute when he fired a powerful drive into the top corner from nine yards out after a deft lay off from youngster Mohamed Ibrahim, who came on as a second-half substitute.
Fathallah rose at the near post to capitalize on a mis-timed jump from keeper Kamal and head home Shikabala's corner seven minutes from time, taking his tally to three goals so far this season.
Zaki could have made sure of victory on a couple of occasions but squandered his easy chances. Zamalek held on though to maintain their fine run of late.