Chris Katongo pulled one back for the home side after Matsatsantsa had gone 1-0 ahead, but substitute Manyama’s strike proved the difference.
SuperSport coach Gordon Igesund made two changes to his team that lost 4-1 to Maritzburg United in midweek, with Mor Diouf coming in for the injured Thamsanqa Teyise and Thato Mokeke replacing Lebogang Manyama.
Meanwhile, Gavin Hunt made four changes to his Wits side that lost to Polokwane City in midweek. Sameehg Doutie dropped out the team due to him being on loan from SuperSport to Wits and not allowed to play against his parent club in cup games.
It took only two minutes for a goal to come when SuperSport hit the home side on a counter-attack after Wits gave the ball away at a corner-kick. Dino Ndlovu broke free and passed to Wome who made no mistake.
But the Clever Boys were back in it after 12 minutes when Henrico Botes did well to put Katongo through on goal and the experienced Zambian slotted easily past Ronwen Williams, who slipped as he rushed off his line.
Katongo came close again in the 19th minute when his flick beat Williams in goal and crashed off the woodwork.
In the 32nd minute Williams did well to save Sibusiso Vilakazi’s free-kick before Ndlovu almost got round Moeneeb Josephs to score on the other end for the visitors.
Two minutes into the second half and Ndlovu came close to number two for the visitors, but moments later he had to be substituted after take a blow to the face with the ball and was knocked unconscious.
On the hour-mark Wits keeper Moeneeb Josephs made a great save to deny Manyama from close range after he struck the ball sweetly following a low cross into the box.
But five minutes later SuperSport did grab their second goal when Manyama cut inside Buhle Mkhwanazi and fired in a low shot past Josephs following yet another swift counter-attack.
This time, SuperSport scored after soaking up a flurry of attacks on their own goal by Wits’ attacking players.
Wits threw everything forward in search of an equaliser in the final ten minutes, but it was not to be.