AmaZulu took the lead in the seventh minute when Bongi Ntuli grabbed his 13th goal of the season. Lehlohonolo Majoro was played in down the right-hand side and cut the ball back across the turf in to the box for Ntuli to softly side-foot in to the bottom right-hand corner back of the net.
Majoro missed an absolute sitter in the 19th minute when he kicked clean air with the goal at his mercy after being found umarked at the back post by Siyethemba Sithebe's inch-perfect cross.
Majoro once again turned provider for Ntuli, playing in his strike partner down the right-hand side but Usuthu's top goalscorer badly shanked his effort well wide of the post.
Usuthu came close moments later after Leopards goalkeeper King Ndlovu spilled the ball in the box before he redeemed himself by saving Edwin Gyimah's follow-up effort.
Right on the stroke of half-time, Hlongwane's corner was flicked on by Mwape Musonda in to the path of Gyimah, who blazed the ball over the bar on the volley from close range.
Thabo Matlaba's cross in to the area caused all sorts of chaos for the Usuthu defence in the 53rd minute with Mbatha fluffing his attempted punch but luckily for him, Tumelo Khutlang was unable to make anything of the opportunity.
With 15 minutes left on the clock, Khutlang's cross found Musonda at the back post, with the Zambian doing well to outjump his marker but unfortunately for Leopards, he was unable to direct the header on target.
But in the end, Lidoda Duvha were unable to find the much sought-after equaliser despite exerting plenty of pressure late on as Ayanda Dlamini guided his team to a massive win.
The crucial three points means Usuthu climb from 15th to 13th and three points clear of the drop zone, while Leopards drop to 14th and are now just one point above the drop zone.
Leopards: Ndlovu, Mudau, Zulu, Masia, Gyimah, Abubakar, Ng'ambi, Hlongwane, Matlaba, Musonda, Khutlang.
Subs: Mendes, Ndawonde, Ndou, Mokoena, T. Ndlovu, Makgetlwa, Thutlwa, Andrianarimanana, Mncwango.