Pirates substitute Lehlohonolo Majoro opened the scoring in the 68th minute with his second touch of the game, but Maarouf Youssef and Mostafa Fathi hit back for the Egyptian giants at Mbombela Stadium.
The White Knights now top Group B with six points from two matches - three points ahead of Bucs, and five in front of CS Sfaxien and AC Leopards, who drew 1-1 in Sfax last night.
Eric Tinkler's men will next visit Tunisian outfit Sfaxien on July 25.
The CAF tie started at a frenetic pace, with Zamalek dangerman Ayman Hefny firing over as early as the first minute.
Pirates, however, nearly scored two minutes later, but Thamsanqa Gabuza was foiled by the upright when getting on the end of Thabo Rakhale's cross from the right.
At the other end, Nigerian midfielder Youssef clipped the side-netting with a speculative effort on the angle to keep Brighton Mhlongo on his toes.
Gabuza threatened again midway through the stanza, but his left-footed attempt lacked power after stepping in off the right flank with intent.
The Sea Robbers continued to press, as marauding left-back Thabo Matlaba rattled a cross-cum-shot past the face of goal before drawing a low save from Ahmed El-Shenawy in the 36th minute.
Oupa Manyisa came close shortly after as he thundered a strike just off target from range for the hosts.
Sifiso Myeni nearly struck on the stroke of half-time, as he stabbed narrowly wide after being wonderfully teed up by striker Kermit Erasmus.
Zamalek showed more initiative after the interval, as Basem Morsi twice directed efforts wide leading up to the hour-mark.
The visitors, nevertheless, fell behind when Majoro raced on to Myeni's sublime pass and cooly slotted the ball past El-Shenawy moments after replacing Erasmus.
However, the five-time tournament winners replied four minutes later, as Youssef rifled a blistering strike into the roof of the net after being set up by Morsi.
Fathi then decided affairs with a fantastic curling effort in the 84th minute, with El-Shenawy pulling off two fine stops at the death to deny Matlaba and Happy Jele.
Zamalek: El-Shenawy, Tolba, Ali Gabr, Kofi, Samir, Salah, Maarouf, Tawfik, Hefny, Eid, Morsi.