Goals from Ahmed Tawfik, Ahmed Mekki, Mostafa Fathi and Mahmoud Kahraba overshadowed Oupa Manyisa's goal in the first half to ensure Zamalek walk away with the three points in Cairo.
Pirates had the first opportunity of the match in the third minute through Sifiso Myeni but Mahmoud Genesh was up to the task as he held onto the midfielder's tame effort.
The home side should have been 1-0 up in the 10th minute but Mohammed Ibrahim was denied only by Ovono's upright.
Three minutes later Zamalek found the opener through Tawfik after poor defending from Pirates saw the midfielder in acres of space to hit the back of the net.
Bucs finally upped their tempo and were rewarded in the 32nd minute after Manyisa volleyed home a lovely cross from Thamsanqa Gabuza.
The joy did not last long as the hosts broke through the Pirates defence with ease once more, as Mekki's run went unmarked to beat Ovono and restore Zamalek’s lead.
Tinkler made a double sub in the 58th minute, bringing on Kermit Erasmus and Menzi Masuku in place of Gabuza and Issa Sarr, to show clear attacking intentions.
Five minutes later Zamalek were again on the scoresheet as substitute Fathi scored with his first touch after great work from Kahraba down the left wing.
The Egyptian giants put the tie beyond the Buccaneers as Kahraba completed a man of the match performance with a goal of his own in the 67th minute.
Despite the scoreline going unchanged, Ovono was kept busy in goal as Zamalek continued their onslaught of a makeshift Pirates defence.
Mekki had a chance to complete his brace but Ovono did well to deny the striker from point-blank range with three minutes to go.
The result sees Zamalek finish top of Group B with 15 points while Pirates remain second with 12 points.
The South African side will now face Al Ahly in the two-legged semi-finals of the CAF Confederation Cup, with the first leg being at home.
Pirates: Ovono, Matlaba, Sangweni, Jele, Phungwayo, Rakhale, Ntshumayelo, Sarr (Masuku 59'), Myeni (Makola 79'), Manyisa, Gabuza (Erasmus 58')
Subs: Mahamutsa, Nyauza, Masalesa, Makola, Erasmus, Majoro, Masuku
Zamalek: Genesh, Tolba, Kofi, Ali Gabr, Gaber, Hamed, Maarouf, Tawfik, Kahraba, Ibrahim, Mekki
Subs: Ali Gabol, Dowidar, Gomaa, Hazem, Hamoudi, Fathi, Hefny