Following a rain-affected second day, the Windies started their reply to South Africa's first-innings total of 552-5 declared on Friday, and quickly crumbled as the tourists were bowled out for 201.
Seamers Vernon Philander (4-29) and Morne Morkel (3-55) ripped through the visitors' batting line-up at will, with no visiting batsman able to reach 50 in a meek surrender from Denesh Ramdin's men.
Sensing triumph, the hosts enforced the follow on and promptly edged closer towards claiming a lead in the three-match series as Philander and Morkel picked up an extra wicket apiece.
No further inroads were made by the South Africa attack before the close but, with the Windies still trailing by 275 runs on 76-2, a substantial home win now looks inevitable.
The visitors appeared to be in a position to at least post a competitive total as openers Kraigg Braithwaite (34) and Devon Smith (35) put on 72 in their opening partnership.
However, South Africa - depleted in the field due to an ankle injury to wicketkeeper Quinton de Kock and Faf du Plessis' illness - soon took control as both batsmen were removed by Philander.
Smith was unfortunate to be given out caught behind on review despite not appearing to strike the ball with his bat, but his departure did not spark an immediate collapse.
Leon Johnson (31) and Marlon Samuels (33) both offered the Windies hope, but that was all but extinguished after the latter chopped on to his stumps from Morkel to reduce the score to 162-4.
From there the tourists never looked like recovering as they lost five wickets for just 39 runs, with a tail lacking the presence of the injured Kemar Roach capitulating with minimal resistance.
The ineptitude of the Windies' batsmen left South Africa captain Hashim Amla with an easy decision to make, and the move to keep them at the crease was soon vindicated.
Smith (five) edged a Philander delivery to the slips in the fourth over of the second innings before Braithwaite (20) fell victim to a stunning catch from Alviro Petersen off the bowling of Morkel.
The status of De Kock and Du Plessis is to be monitored overnight, and although Dale Steyn and Philander are both experiencing tightness, there seems to be little to prevent South Africa from claiming a 1-0 lead.