The visitors went close to breaking the deadlock after nine minutes when Sifiso Hlanti's low strike sailed inches wide of Reyaad Pieterse's upright.
SuperSport settled into the game after 15 minutes, as they enjoyed a lion's share of the possession.
On 20 minutes, the hosts were awarded a penalty when Thulani Hlatshwayo was adjudged to have handled in the box. Dean Furman stepped up and made no mistake from the spot, 0-1.
With 15 minutes remaining in the half, Gavin Hunt's troops started seeing more of the ball but they found it tough to break down the SuperSport defence as they went into the break trailing.
SuperSport went agonisingly close to doubling their shortly after the break as Kingston Nkatha rattled the crossbar with a volley from 25-yards out.
A minute later, Wits levelled matters when poor defending allowed Gabadinho Mhango to sneak in fire past Pieterse in the six-yard box.
The Absa Premiership champions then took the lead on 53 minutes when James Keene rose above two markers to send a header to the far post, 1-2.
It was 3-1 on 64 minutes when Mahango turned provider to tee up Daylon Claasen, who rifled the ball into the top corner from 20-yards out leaving Pieterse with no chance.
SuperSport were no match for the Clever Boys in the second half as they failed to threaten goalkeeper Darren Keet. in the second stanza.
Wits skipper Hlatshwayo rounded off the scoring for the visitors in the 87th minute with a towering header in the six-yards out as the champions ran out big winners on the night.