Wicket-keeper Mark Boucher followed up with a run-a-ball 55 not out as the Proteas scored 60 runs in the last 10 overs.
Part-time spinner Yuvraj Singh took three for 36 after fine new-ball bowling from fellow left-armers Zaheer Khan and RP Singh.
The Proteas had been in trouble at seven for two and 46 for three after losing the toss in seam bowler friendly conditions.
But a fourth-wicket stand of 85 between van Wyk, batting in place of injured regular captain Graeme Smith, and Jean-Paul Duminy (40) repaired some of the early damage after Jacques Kallis and Herschelle Gibbs both fell cheaply.
It wasn't until the fourth over, with a RP Singh wide, that South Africa had their first runs but, next ball, India had their first wicket.
Van Wyk set off for a single but stopped with non-striker AB de Villiers well down the pitch.
RP Singh, reacting quickly, gathered the ball and threw to the non-striker's end where Dravid took off the bails and de Villiers, ruled not to have grounded his bat by third umpire Aleem Dar, was out for nought.
New batsman Kallis, who'd made 91 not out in the Proteas's four-wicket win in the opening fixture of this three-match series on Tuesday, scored the first run off the bat in the fifth over with an unconvincing inside edge.
But, on two, the South Africa captain dragged a full-length delivery from RP Singh onto his stumps.
Khan was replaced by 18-year-old debutant Ishant Sharma, who only arrived in Belfast on Wednesday and the fast bowler tired towards the end of a seven over spell costing 38 runs.
It was Khan who captured the prize wicket of Gibbs when the batsman drove his third ball back powerfully off the backfoot straight to Dinesh Karthik, normally a wicket-keeper, at cover.
Piyush Chawla, the 18-year-old leg-spinner who'd taken three for 47 on Tuesday, saw Van Wyk loft him for the first six of the innings in his second over.
Van Wyk completed his fifty in 87 balls with one six and five fours.
It was his second one-day international half-century in a week after he made 52 in the 42-run win against Ireland on Sunday.
Left-hander Duminy offered solid support but a lapse in concentration cost him dear when he cut Yuvraj's third ball straight to Dravid at backward point, having faced 59 balls with three fours.
At 166 for four off 40 overs, South Africa were better placed for a late charge than they could have hoped for earlier in their innings.
But Van Wyk, who until this trip had gone four years without playing a one-day international since his debut against England at Lord's, fell in the next over.
The 28-year-old bottom-edged a cut and was well caught, low down, by fit-again wicket-keeper Mahendra Singh Dhoni, the first India player to fall victim to the flu bug that had run through the squad.
Van Wyk faced 126 balls with one six and seven fours.
Boucher struck Chawla for six as he gave South Africa's attack something to bowl at.