AmaZulu started with a front-two of Bonginkosi Ntuli, Siphelele Mthembu and Luvuyo Memela, Philani Zulu and Sandile Khumalo complemented matters from the goalless draw with SuperSport United.
Usuthu bounced back from the first-leg loss with a fourth minute lead from the penalty spot by Ntuli, who converted comfortably after the referee called a handball on the goal-line.
Ntuli, who hadn't start any official clash prior to this encounter, snatched a brace after seven minutes with a clever back-heel finish from smart work by his strike-partner Mthembu.
Big Bullets looked to get a way back as the first half began to wind down, whilst Usuthu made a forced substation on 38 minutes with Zulu withdrawn and Makhehlene Makhaula introduced.
The Malawian side halved the tally five minutes in the second stanza through a powerful free-kick from Henry Kabuchi following a coming-together.
Usuthu earnestly restored their two-goal advantage through a neat finish in the six-yard area from Mthembu off a layoff by Ntuli and clever run by Memela too.
Big Bullets still showed courage amidst the score-line and worked saves off goalkeeper Veli Mothwa as Usuthu introduced veterans such as Tsepo Masilela, Keagan Buchanan and Lehlohonolo Majoro.
The South African outfit had no issues running down the closing stages of the match though, which led them to victory and a date with TP Mazembe in the next phase of the CAF Champions League.