Tanzanian import Mbwana Sammatta and Democratic Republic of Congo international Deo Kanda scored second half goals to beat Al-Ahly of Egypt 2-0 in their Group A game in Lubumbashi.
The victory means Mazembe join their Egyptian opponents on 10 points from five matches, and both can no longer be caught with one round of group games still to be played.
Ghana's Berekum Chelsea are eliminated along with Zamalek of Egypt after they played out a 1-1 draw in Cairo on Saturday.
The top two places in Group B have already been decided after the Confederation of African Football last week expelled Etoile Sahel of Tunisia following the rioting of their supporters.
Defending champions Esperance of Tunisia and Nigeria's Sunshine Stars are therefore guaranteed to progress to the final four.
The semi-final pairings will be decided at the completion of the last round of group matches on the weekend of September 14-16.
The semi-finals will be played over two legs in October.