New additions Khanyisa Mayo and goalkeeper Hugo Marques started for City against Usuthu, who also handed debuts to recent signings Philani Zulu and Keagan Buchanan.
The Citizens grabbed the lead on eight minutes after Terrence Mashego ran unchallenged from the left-side of the offensive area to fire in off the far post.
Another surge towards the home side's area saw Thato Mokeke coming close to double City's lead inside a minute, but AmaZulu goalkeeper Veli Mothwa made a solid block.
Usuthu could've turned matters level on the stroke of halftime through Siyethemba Sithebe from a clever position around the danger area, but he snapped Luvuyo Memela's supply wide.
City coach Eric Tinkler was the first to turn to the substitutes bench ahead of the second half and brought on Tashreeq Morris in place of Craig Martin.
However, Usuthu managed to claw themselves back on level terms nine minutes into the resumption with a finish from Lehlohonolo Majoro following a ball by Buchanan.
Substitute Morris was on the receiving end of a good chance to put City back in front a moment afterwards, but he was caught in two minds and saw the chance missed.
AmaZulu threatened to go in front in the last eight minutes with a free-kick from Tapelo Xoki, but Marques palmed away for a corner-kick as the game began to open up.
The Citizens secured the winner two minutes from time when Mduduzi Mdantsane worked his way into the area before finding out the bottom-corner.
AmaZulu: Mothwa, Sikhakhane, Zulu, Xoki, Mgwazela, Makhaula Sithebe, Buchanan, Majoro, Memela, Mulenga.
Subs: Mzimela, Moleko, Khumalo, Kunene, Moremi, Maduna, Mlambo, Mthembu, Ntuli.
City: Hugo, Mkhize, Fielies, Mobara, Mashego, Mokeke, Mdantsane, Makola, Martin, Ralani, Mayo.
Subs: Mpandle, Mapfumo, Cupido, Morris, Nodada, Makhuoane, Roberts, Diana-Olario.