AmaZulu woke up after a pedestrian first half performance to suddenly take charge of the game after the break and progressed with goals from Emiliano Tade and Bongi Ntuli, which ended a run of five matches without success.
The first half was characterised by both teams pressing each other into a myriad of mistakes with a heady turnover of possession and little opportunities in front of goal.
City looked perhaps the slicker of the two sides on the ball with AmaZulu rarely getting into the attacking third through the first 45 minutes.
But they did get a fortuitous chance midway through the first half when City skipper Thamsanqa Mkhize gave away the ball and Tade was allowed a shot at goal.
The rebound fell for Ntuli whose effort went past goalkeeper Sage Stephens but was cleared before it got near the line by City defender Keanu Cupido.
After the break, it took until past the hour mark for the first chance as Tade had a belter blocked by Kwanda Mngonyama.
But almost immediately the Argentine import broke the deadlock after a darting run down the right from Thembela Sikhakhane who perfectly placed the ball back for Tade to calmly slot it away in a lesson in how to finish that local strikers can learn from.
The 62nd minute opener was quickly followed by an opportunistic finish from Ntuli, who took advantage of hesitation from Mngonyama in clearing a throw-in and nicked in around him to squeeze the ball past Stephens.
The result was sealed after that as City never looked like fighting back and went limply out of the competition at the first hurdle, just weeks after winning the MTN8.
TKO Quarterfinal fixtures:
Kaizer Chiefs vs SuperSport United
AmaZulu vs Orlando Pirates
Maritzburg United vs Bidvest Wits
Baroka FC vs Mamelodi Sundowns