Champions in 2009 and 2010, Mazembe defeated Al Hilal Omdurman 3-1 to ensure their challenge for a third title in six years continued apace.
Al Hilal came into the game under the guidance of Al-Tag Mahgoub following the sacking of Paulo Campos for his behaviour towards match officials last time out against V.Club.
Mahgoub was unable to inspire his side to victory, however, as Rainford Kalaba put the Congolese outfit ahead in the 27th minute after being set up by Solomon Asante, who doubled the advantage on the hour mark.
Adama Traore put the result beyond doubt 14 minutes from the end, with Mudather El Tahir's stoppage-time consolation failing to spoil the Mazembe party.
In the other game in the pool, Yunus Sentamu's 55th-minute strike was enough to seal a 1-0 win for V.Club that completed a torrid few days for Zamalek.
The Egyptian giant's preparations were disrupted when a group of fans stormed the club's headquarters and vandalised chairman Mortada Mansour's office after he had publicly criticised their attitude.
New coach Hossam Hassan, who replaced Mido last week, could not rally the side into securing the result they needed to keep their qualification hopes alive as the 2002 winners duly crashed out.
Sunday's results mean Mazembe and V.Club are level at the top of the group with 10 points from five matches.
The winner of the all-Congolese clash between the two sides on matchday six will determine who progresses as group winner to the semi-final, with CS Sfaxien and ES Setif already assured as the teams that lie in wait from Group B.
