As expected Kwesi Appiah included key players, Thomas Partey, Andre and Jordan Ayew in the starting line-up as the Black Stars looked to begin their qualifying campaign with a win.
Appiah's counterpart, Molefi Ntseki named Percy Tau, Thembinkosi Lorch and Bradley Grobler as the front three, while Thabo Mokeke surprisingly started ahead of Thulani Serero.
Ghana dominated possession in the opening exchanges with Partey pulling the strings from midfield for the Black Stars.
The hosts came close to scoring when Partey's free-kick was flicked on by Jordan Ayew, but Bafana Bafana goalkeeper Ronwen Williams made a comfortable save.
South Africa grew in confidence as the match progressed and they had a chance to break the deadlock through their main striker Grobler.
The ball fell kindly for the SuperSport United hitman inside the box, but he fired over the crossbar without troubling Richard Ofori in the Ghana goal-posts.
However, the visitors suffered a big blow for Bafana as Bongani Zungu limped off the pitch and he was replaced by Thapelo Morena just before the half-hour mark.
Ghana then broke the deadlock in the 35th minute through Partey, who beat Williams with a deflected long-range shot making it 1-0 to the home side.
Ofori then produced a fine low save to deny Tau to ensure that the first half ended with Ghana leading 1-0.
The Black Stars controlled the match after the restart with Ayew causing havoc for the Bafana defence with his clever movement around the box.
The Crystal Palace marksman's effort was blocked at the far-post by Lorch, before he curled his effort inches wide of the target.
Ntseki, who was taking charge of his maiden competitive game as Bafana coach, introduced strikers Lebogang Mothiba and Kermit Erasmus as the visitors searched for the equalising goal.
South Africa attacked in numbers in the closing stages of the match, but they were struggling to create chances and they were also left vulnerable at the back.
They were punished by 19-year-old debutant Mohammed Kudus, who made a run from midfield before firing past a hapless Williams to make it 2-0 to Ghana with 11 minutes left.
Appiah's men then sat back and contained the visitors, who found it difficult to penetrate the hosts' defence and ultimately, Ghana recorded a 2-0 victory.
Ghana will now be away to Sao Tome and Principe in their next Group C match on Monday, while South Africa are set to host Sudan on Sunday.