Dynamos of Zimbabwe did the Congolese club a huge favour by clinching a 1-0 win against Entente Setif, who forced a draw at Mazembe two weeks ago and could have posed a serious threat had they taken maximum points in Harare.
Mazembe have seven points in Group A, Esperance six, Dynamos three and Setif one at the halfway stage of a mini-league from which the winners and runners-up qualify for the semi-finals of the premier club competition on the continent.
Lacking inspirational captain and leading scorer Mabi Mputu, and midfielder Basisila Lusadisu through suspension, Mazembe fell behind late in the opening half when Michael Eneramo struck in Lubumbashi.
It was the fifth goal of the campaign for the 24-year-old Nigerian striker, putting him alongside team-mate Wajdi Bouazzi and Mandela Ocansey from Burkina Faso club ASFA Yennenga as the leading CAF Champions League scorers.
The Congolese hit back swiftly to equalise through midfielder Alain Kaluyituka before half-time and veteran striker Ngandu Kasongo scored the winner four minutes from full-time after an action-packed second half.
Setif made the long journey south to the Zimbabwean capital confident of success having followed up the draw with Mazembe by defeating CS Sfaxien of Tunisia 1-0 to lift the North African Super Cup.
Desperate Dynamos had other ideas as they knew only a win would keep them in contention for a last-four place following losses to Mazembe and Esperance in previous rounds.
The Harare Glamour Boys dominated the first half and midfielder Wonder Sithole put recent poor form behind him by scoring the only goal after 30 minutes at Rufaro Stadium.
It was a superb solo effort from Sithole who beat several Algerian defenders before unleashing an unstoppable drive from outside the penalty area that left the visiting goalkeeper helpless.
Coping well without injured playmaker Desmond Maringwa, 1998 CAF Champions League runners-up Dynamos could have put the issue beyond doubt five minutes from full-time only for unguarded Farai Vimisai to blaze wide. Setif squandered a stoppage-time chance to salvage a point by failing to convert a close-range free kick.
Group B pacesetters JS Kabylie of Algeria host second-placed Al-Ahly of Egypt in Tizi-Ouzou late on Sunday while Ismailia of Egypt have home advantage over fellow strugglers Heartland of Nigeria.