The left-handed De Kock hit 135 off 121 balls in a South African total of 358 for four after the hosts were sent in to bat.
India's top order were blown away by the South African fast bowlers and some sharp fielding.
Despite an innings of 65 by captain Mahendra Singh Dhoni they could only manage 217 in reply, giving South Africa victory and a 1-0 lead in the three-match series.
It was De Kock's second century in his 14th one-day international and the South African wicketkeeper combined power with finesse as he hit 18 fours and three sixes.
De Kock and Hashim Amla (65) shared a first wicket partnership of 152 which laid the foundation for some brutal hitting by De Kock, captain AB de Villiers and JP Duminy in the closing overs.
De Villiers slammed 77 off 47 balls with six fours and four sixes.
He and De Kock added 75 off 55 balls for the third wicket but that was made to look pedestrian as De Villiers and Duminy thrashed 105 off 46 deliveries for the fourth wicket before De Villiers was bowled, going for another big shot, in the final over.
Duminy was unbeaten on 59, made off 29 balls with two fours and five sixes.
With both openers well set, South Africa opted to take the batting power play early, in the 30th over.
But Amla fell to the third ball of the field restrictions, chopping a ball from Mohammed Shami into his stumps.
Jacques Kallis also fell to Shami in the power play after making 10 but there were few moments of cheer for India after that.
Shami was the most successful Indian bowler, taking three for 68.
India were soon under pressure as Dale Steyn started with two maiden overs to Rohit Sharma, who played and missed at a succession of fast away-swingers.
Shikhar Dhawan hit three boundaries off Lonwabo Tsotsobe but tried to pull the first ball he faced from Morne Morkel and was beaten by the extra pace and bounce, ballooning a catch to De Kock off a top edge.
Ryan McLaren struck twice in three balls, having Virat Kohli caught at slip for an aggressive 31 and then bowling Yuvraj Singh with a yorker after softening him up with a bouncer.
Sharma was run out by a direct hit from David Miller at cover in the next over and India, at 65 for four, were in a hopeless position.
Dhoni restored some pride for India, hitting 65 off 71 balls with eight fours and a six before he was ninth man out, the second victim of Steyn, who took the last three wickets to finish with three for 25 in eight overs.
With an all-pace attack, South Africa conceded 24 wides and would have run well over the allotted time for their overs if they had not bowled India out in 41 overs.
Dhoni said at the toss that his decision to send South Africa in to bat was influenced by a forecast of thundershowers. Although storms swirled in the vicinity of the Wanderers play was not interrupted.