The 20-year-old made his second ODI century - the first of which came against Pakistan last month - hitting 18 fours and three sixes.
AB de Villiers (77) and JP Duminy (59 not out) also aided the cause as South Africa smashed 100 runs from the last six overs to finish their innings on 4-358.
Mohammed Shami finished with figures of 3-68, while MS Dhoni contributed a stubborn 65 but India fell well short of the target.
South Africa won the toss at the New Wanderers Stadium in Johannesburg, and that decision paid immediate dividends as Hashim Amla and De Kock put on an opening stand of 152.
The fruitful partnership was brought to an end in the 30th over when Amla (65) played an inside edge onto the wicket from Shami's delivery.
Jacques Kallis could only add 10, but De Kock continued to find the boundary with consummate ease including a fine flat shot straight over midwicket for six off Ravindra Jadeja.
India finally ousted De Kock thanks to Virat Kohli's (1-15) slower delivery that the batsman hit straight back into the hands of the bowler, before exiting the field to a fine reception.
The setback failed to curtail the hosts, however, and with De Villiers and Duminy at the crease the runs piled on.
The duo laid on a partnership of 105, hitting nine sixes between them, before De Villiers was bowled by Shami in the final over.
India's made an inauspicious start to their reply, with Shikhar Dhawan falling for just 12, before Ryan McLaren (3-49) accounted for the wickets of Kohli (31) and Yuvrav Singh (0) in the 15th over.
By the time Rohit Sharma (18) was run out by David Miller, India were reeling on 4-65.
Captain Dhoni came in to steady the ship, hitting eight boundaries and a six in a measured display.
But the partners dried up, with Suresh Raina (14) run out by De Kock, before Kallis (1-20) bowled Jadeja (29).
Ravichandran Ashwin (19) and Bhuvneshwar Kumar (0) were both dismissed in the space of 11 balls, before Dale Steyn (3-25) ended Dhoni's resistance.
The victory was wrapped up when Steyn caught and bowled Shami (0) with the final delivery of the 41st over.
The two sides battle again in Durban on Sunday, with South Africa looking to wrap up victory in the three-match series.