Mazembe dominated Zamalek for 70 minutes but were kept at bay by goalkeeper Abdel Wahed Al Sayed, who made a series of saves to keep the Crows from opening the score.
Coach Lamine N’Diaye, whose team had been plagued with letdowns in the second halves during a loss to Egypt’s Al Ahly and a draw with Ghana’s Berekum Chelsea, made three changes in the second half, bringing in Ngandu Kasongo, Deo Kanda and Hichani Himonde.
The move paid off a few minutes later, Ngandu Kasongo scored on 70 minutes with a left-footed strike. Tanzanian Mbwana Ali Samatta added to the score on 77 minutes with a header.
The win gives the Crows four points in Group B, on par with Berekum Chelsea. Al Ahly extended their lead on top of the group to nine points on Saturday after beating Berekum Chelsea 4-1 in Cairo. Winless Zamalek remain at the bottom of the group with 0 points.
In Group A, Esperance de Tunis beat Etoile du Sahel 1-0 on Sunday, in an all-Tunisian derby in Tunis, while Nigeria's Sunshine Stars won 2-0 against ASO Chief of Algeria in Ijebu-Ode.
After all second leg games are played, the two teams on top of the each group will qualify for the semifinals of the premier continental club competition.