Mazembe, of the Democratic Republic of Congo, won back-to-back titles in 2009 and 2010 and were placed in the same pool as five-time winners Zamalek, who last tasted success in 2002.
With the top two from each group advancing to the semi-finals, the pair will go up against Al Hilal Omdurman and AS Vita Club for a place in the last four.
Group B contains another former winner in ES Tunis, who were last in the final two years ago when they lost to Al Ahly, 12 months after claiming glory with a 1-0 aggregate success over Wydad Casablanca.
They also made the final in 2010, but were beaten by Mazembe, and will now face fellow Tunisian side CS Sfaxien, as well as Algeria's ES Setif and Al Hilal Benghazi, who knocked out defending champions Al Ahly in the second qualifying round.
That defeat meant that Al Ahly took up a place in Africa's secondary competition, the CAF Confederation Cup, and the Egyptian giants were drawn in Group B.
They will face Sewe Sport, Nkana and Etoile Sahel, while Group A includes the winners of the tournament two years ago.
Leopards de Dolisie overcame Djoliba 4-3 on aggregate in 2012 and they will have to see off the challenge of ASEC Mimosas, Cotonsport and Real Bamako if they are to repeat the feat this time around.
Draw in full:
CAF Champions League
Group A: Al Hilal Omdurman (Sudan), TP Mazembe (DR Congo), AS Vita Club (DR Congo), Zamalek (Egypt)
Group B: Esperance Tunis (Tunisia), ES Setif (Algeria), CS Sfaxien (Tunisia), Al Hilal Benghazi (Libya)
CAF Confederation Cup
Group A: ASEC Mimosas (Ivory Coast), AC Leopards (Congo), CotonSport (Cameroon), Real Bamako (Mali)
Group B: Sewe Sport (Ivory Coast), Etoile Sahel (Tunisia), Al Ahly (Egypt), Nkana (Zambia)
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