Dean Elgar (121) posted his third Test ton while Faf du Plessis (99 not out) closed to within??one run of his fourth??as the Proteas battled back from the early loss of Alviro Petersen (17).
But the tourists helped the hosts on their way, with Elgar given two lives following missed stumping and run-out opportunities and Du Plessis dropped twice.
South Africa, victorious in the first Test at Centurion by an innings and 220 runs, were put into bat by a West Indies side who made sweeping changes to their pace attack.
Shannon Gabriel and 32-year-old debutant Kenroy Peters replaced the injured Kemar Roach and the dropped Sheldon Cottrell, while all-rounder Jason Holder, West Indies??? new one-day skipper, was preferred to batsman Jermaine Blackwood.
Gabriel made an impact with his fifth ball when he forced Petersen to hit to Leon Johnson in the covers with the score on 47 in the 12th over, but the visiting bowlers earned just one more reward, mainly due to the wastefulness of their fielders in the second session.
Du Plessis was shelled by Marlon Samuels at gully when he was on eight and put down again by Devon Smith at slip on 26, leaving respective bowlers Jerome Taylor and Sulieman Benn nonplussed.
Elgar, meanwhile, benefitted from a Denesh Ramdin fumble behind the stumps after bounding out of his crease, and the opener breathed a huge sigh of relief later on, too, when Peters threw waywardly towards the poles while he was stranded halfway down the wicket after attempting a suicidal run.
Left-hander Elgar, who top-edged a quick delivery from Gabriel onto his helmet while on 83, brought up three figures by driving Taylor through the point-gully region before he and Du Plessis took their second-wicket partnership to 179.
Elgar eventually became Peters??? first Test victim, clipping a delivery from the Windward Islands seamer into Ramdin???s gloves, but Du Plessis and Hashim Amla (17 not out) held firm until the close.
South Africa made two changes from the team that triumphed in Centurion, with Temba Bavuma replacing the injured Quinton de Kock to become the first black African specialist batsman to play for his country, and veteran leg-spinner Imran Tahir favoured over paceman Kyle Abbott.
AB de Villiers, meanwhile, who is standing in as wicketkeeper in De Kock???s absence, started a record 97th consecutive Test since debut, placing him one game ahead of former Australia gloveman Adam Gilchrist.