The Green Eagles took an early lead through defender Mohamed Hashem, only for ZESCO forward Freddy Kouablan to level the score a minute later.
Algerian forward Mounder Temine restored Masry's lead in the 24th minute, before his compatriot Abderrahim Deghmoum added a third. However, midfielder Peter Musukuma netted a late consolation goal for the hosts.
Masry kicked off their group stage campagin with a 2-1 home win over South Africa's Kaizer Chiefs on Sunday, while ZESCO suffered a narrow 1-0 defeat to Egyptian side Zamalek on the same day.
The Port Said club started cautiously, relying on a solid defence and speedy counter-attacks to absorb pressure from the hosts.
Hashem broke the deadlock after just four minutes, capitalising on a rebound from ZESCO goalkeeper Phillip Sakauta.
Kouablan immediately equalised for ZESCO following a defensive blunder from Masry keeper Mahmoud Hamdy and defender Hashem.
Temine then put Masry ahead again in the 24th minute, pouncing on a mistake by the ZESCO defence.
The Zambian champions piled on the pressure after the break, but Masry keeper Hamdy produced a series of fine saves to keep them at bay.
Deghmoum extended Masry's lead in the 68th minute, finishing off a precise cross from Temine following a quick counter-attack.
ZESCO's persistent pressure finally paid off as Musukuma pulled a goal back with a brilliant solo effort from the right flank.
The victory sees Masry maintain the Group D summit with a maximum six points, ahead of second-placed Zamalek, who will face South Africa’s Kaizer Chiefs on Saturday.
Masry are set to take on Zamalek in the third round on 25 January.
(For more sports news and updates, follow Ahram Online Sports on Twitter at @AO_Sports and on Facebook at AhramOnlineSports.)
Short link: