The Chiefs goals were scored by Lehlohonolo Majoro and a brace from Bernard Parker while Calvin Kadi scored for Wits.
Chiefs were the better side in the first-half, but the Clever Boys will be disappointed that they failed to convert most of the good chances they created after the break.
The first chance of the match fell for Kingston Nkhatha in the 8th minute as he did well to control a long pass from Siboniso Gaxa, but the Zimbabwean was denied by a good save from teenage goalkeeper Steven Hoffman.
However, Chiefs did manage to break the deadlock five minutes later as Parker bundled the ball in at the far post, following some good work from George Lebese on the left.
Nkhatha would have another chance to get his name on the score sheet in the 32nd minute, but he sent his shot wide before Siphiwe Tshabalala did the same on the stroke of half time.
However, the lead was doubled in the 36th minute when the Wits defence failed to clear a cross from Gaxa, allowing Lebese to feed Parker who then shot past Hoffman to grab his brace from close range.
The second half saw Wits seeing most of the ball possession and keeping the Chiefs defence on their toes as substitute Asive Langwe attacked on the right, while Kadi operated on the left.
The latter was unfortunate not to reduce the deficit in the 53rd minute after meeting a Bryce Moon cross with a powerful header, but Khune was at the right place at the right time to keep the ball from going over the line.
Fourteen minutes later it was Langwe who went on a superb run through the defence before finding Matthew Pattison unmarked near the penalty spot, but the former Mamelodi Sundowns man ballooned his shot over the crossbar.
Then in the 69th minute Erwin Isaacs tested Khune with a stinging long range effort, but the Bafana Bafana goalkeeper was equal to the task as he kept the ball from sneaking inside his left post.
Wits were eventually rewarded for their positive play in the second half ten minutes from the end of regular time when Kadi came flying in to volley home from another brilliant cross from Langwe.
Nevertheless, Wits chances of claiming a point from the game were ended in the 89th minute when Reneilwe Letsholonyane played the perfect ball to find Majoro on the right, who made no mistake as he calmly slotted past Hoffman to seal the win for Amakhosi.