The champions were given a bye in the opening stage, but that advantage has been negated by a match-up with Rwanda's most successful club side, APR FC, who have won the Cecafa Clubs Cup in 2004 and 2007.
The weekend's second round, first leg ties across the continent sees the arrival of several of the other favourites, including Egypt's Al Ahly and last year's runners-up Heartland FC of Nigeria in the competition.
SuperSport United will be hosting Mozambique's Ferroviario Maputo.
TP Mazembe only started their domestic campaign in the last month but have already been handed massive affirmation of their new found status in African football.
They won the CAF Africa Super Cup over Stade Malien last month and then last week were named Club of the Year at CAF's annual awards in Ghana.
Indeed, they have further improved their squad since last November's Champions League triumph, adding Zambia midfielder Stopirra Nsunzu to their ranks, who was previously on the books of Chateauroux.
Egyptian giants Al Ahly's first Champions League appearance this year is at Gunners FC in Harare on Saturday; one of three matches to take place in the Zimbabwe capital this weekend, while Heartland are away at Tiko United, who won the Cameroonian league title for the first time last season.
Hopes are high for last year's silver medalists after Nigeria saw their other representatives in this year's campaign embarrassingly eliminated in the first round.
Bayelsa United lost to Gazelle, whose reward is a tough home game against Al Merreikh from neighbouring Sudan.
There are 11 clubs from North African countries still remaining, with all of them having the pedigree to go on and win the competition. However, there will be a few casualties after this round, as the draw paired a few of those contenders together. Tunisia's Club Africain host JS Kabylie while Libya's are up against debutants Difaa El Jadida from Morocco.
JSK traveled early to Tunis this week to prepare for Friday's first leg with coach Alain Geiger hoping for a positive performance.
"To play an away game is no advantage but you need to play both legs at a high level in order to qualify," said the former Swiss international.
"It is true that Club Africain are doing well in their domestic championship and are in form, but this is a completely different competition."
Botswana's Gaborone United were giant killers in the first round by eliminating Orlando Pirates, but the reward for coach Manfred Chabinga has been the sack. The former Zambian international was on three months' probation in the role, but club officials were unhappy with his overall results, despite the fact that they achieved arguably their highest-profile victory in their history by knocking out Orlando Pirates.
In his place comes former Botswana national team coach David Bright, who has returned home after several seasons coaching in South Africa.
The weekend CAF fixtures are: Today: Al Ittihad (Libya) - Difaa El Jadida (Morocco) Club Africain (Tunisia) - JS Kabylie (Algeria)
Saturday: Curepipe Starlight (Mauritius) - Gaborone United (Botswana) Gunners (Zimbabwe) - Al Ahli (Egypt) Ismailia (Egypt) - Stade Tamponnaise (Reunion) APR FC (Rwanda) - TP Mazembe Englebert (DR Congo, holders) SuperSport United (South Africa) - Ferroviario Maputo (Mozambique) Esperance (Tunisia) - ASFA Yennenga (Burkina Faso) Tiko United (Cameroon) - Heartland FC (Nigeria)
Sunday: Africa Sports (Ivory Coast) - Al Hilal (Sudan) Djoliba (Mali) - ASC Linguere (Senegal) Raja Casablanca (Morocco) - Petro Atletico (Angola) Union Douala (Cameroon) - Entente Setif (Algeria) FC St Eloi Lupopo (DR Congo) - Dynamos (Zimbabwe) Gazelle (Chad) - Al Merreikh (Sudan)
The return legs will be played between April 2-4.