Hussein Yasser put the White Knights ahead only after 42 seconds but Sherif Abdul-Fadil hit Ahli's equalizer on 17 minutes.
Mohamed Fadl fired Ahli upfront seven minutes from halftime before Mohamed Abou-Treika ensured their superiority with a 52nd-minute strike.
Having won the Cairo Derby, Ahli set up a quarter-final clash with Petrojet who beat Canal Mooring & Lights 2-0 earlier on Wednesday.
The Red Devils' victory is their eighth consecutive over Zamalek in the Egyptian Cup, 13th overall.
The Whites haven't defeated their neighbors in the Egyptian Cup since the 1958-1958 season.
Ahli, who won the Egyptian Premier League title weeks ago, seem to be poised for a double.
Zamalek, on the other hand, have finished the season empty-handed like the previous one.
Fiery Start
The match witnessed a fiery start as Zamalek's Yasser hit an opener against his former club right after the kick-off.
Ahmed Gaafar darted unmarked down his right-hand flank to whip in a low cross that went past Sherif Ekrami to find Yasser, who made no mistake from point-blank range.
Both teams exchanged attacks for a while later but Ahli clearly had the upper hand despite the early goal they conceded.
The Egyptian champions' first scoring chance fell to Ahmed Shehab, who received a Sayed Moawad cross inside the area but Abdul-Wahed Al-Sayed produced a nice save to prevent the youngster from scoring.
Zamalek's Ibrahim Salah sustained a shoulder injury on the quarter-hour mark to make way for Sabri Rahil, right before Ahli hit their leveler.
Abdul-Fadil rifled a curling and powerful free kick that hit the top corner of the net from around 30 yards.
Ahli took a stranglehold on the game after the equalizer while Zamalek's form notably plummeted.
Ahmed Hassan tried his luck near the edge of the area but Al-Sayed denied his low effort.
Minutes after the half-hour mark, Barakat took advantage of the airy space to run towards Al-Sayed and create a one-on-one chance. The inform in-form goalie once again rose to prominence though.
A follow-up effort from Abou-Treika was blocked by Zamalek's defenders.
Afterwards, Abou-Treika chested a Hassan cross inside the area but mis-hit his shot to see the ball fall into the path of Fadl who easily poked home.
Before scoring Ahli's second, Fadl sustained a facial injury upon being elbowed by Mahmoud Fathallah, who's having his head bandaged up for suffering a severe wound in a league game a couple of weeks ago.
Veteran defender Wael Gomaa was also caught in the face earlier in the first period and was bleeding too.
Both Gomaa and Fadl received treatment on the sidelines and played the whole 90 minutes.
Toothless and Defenseless
Hossam Al-Badri's men further tightened their grip on the match after the break whereas Zamalek completely collapsed and seemed to be toothless and defenseless.
Ahli's onslaught paid dividends soon after the restart.
Abou-Treika headed an Abdul-Fadil shot into the net to give the Egyptian champions a two-goal cushion.
Ahmed Fathi, who has just recovered from a groin problem, was introduced instead of Egypt skipper Hassan, before Abou-Treika made way for Francis Doe.
Gilberto also replaced left winger Sayed Moawad. All three substitutions turned out to be fruitless.
Zamalek tried to reduce the arrears in the last five minutes.
They threatened their opponents several times but couldn't make any changes to the score sheet.