The city side flew to Johannesburg for the round-of-32 first leg after a 2-2 league draw against defending champions Young Africans SC with a second-half John Bocco goal salvaging a point.
The team trained by Stewart Hall is currently placed third in the 16-team Mainland Premier League with 47 points. Archrivals Simba and Yanga are placed first and second, respectively.
Azam FC will have the services of their regular strikers Bocco, Kipre Tchetche, Farid Musa, Mudhathir Yahya, Himid Mao and Salum Abubakar, to seek to beat the home side.
Goalie Aishi Manula will be on guard as usual while the defence all shall predictably comprise Shomari Kapombe, David Mwantika, Saidi Morad, Paschal Wawa and Jean-Baptist Mugiraneza.
The unfashionable Johannesburg Wits were unexpectedly eliminated by teams from regional underdog sides from Madagascar (twice) and Swaziland in previous appearances.
Most humiliating was the preliminary-round exit to Swazi police side Royal Leopard last season as the South Africans surrendered a 3-0 first-leg lead before losing on penalties.
That shock triggered accusations that coach Gavin Hunt did not pick his best players and was not taking regional sides seriously.
Hunt, a three-time Premiership-winning coach with SuperSport United before joining Wits, insists he respects Azam FC because it is a good team with quality footballers.
"Bocco is known to me because he had trials at SuperSport while I was there," said the 51-year-old former Premiership full-back.
Wits warmed up with a 1-0 league win at Polokwane City that trimmed the gap between them and leaders Mamelodi Sundowns to seven points with eight rounds remaining.
Wits hope England-born James Keene can increase his goal haul after scoring seven in league and cup games since a mid-season move from Sweden.
Wits outclassed Light Stars of Seychelles 6-0 and 3-0 in a preliminary tie while Azam FC received a bye in the second-tier CAF club competition.
Whoever qualifies will almost certainly face Esperance of Tunisia, five-time CAF title winners and the strongest looking team among the 32 contenders.