The Proteas batted first at a sweltering Wankhede Stadium in Mumbai and made an awesome 438-4, the fourth-highest ODI total on record and the highest ever scored in India.
Left-handed opener de Kock hit 109, de Villiers notched 119 and du Plessis smashed 133. It was only the second time in a one-day that a trio of batsmen from the same team made three figures.
Hosts India could only manage 224-10 in reply.
De Kock was first to take advantage of a favourable pitch and some woeful Indian bowling to notch his eighth one-day century and his second of the series off 87 balls.
The 22-year-old put together a formidable partnership with du Plessis, who came on after Hashim Amla was caught for 23, as the batsmen combined for a second-wicket stand of 154 runs.
De Kock reached 50 with a risky single in the 13th over and then survived a scare moment later when Mohit Sharma fumbled a catch after misjudging the flight of the ball.
He reached 100 off 78 balls in the 35-degree-Celsius (95 degrees Farenheit) heat, but was made to walk when he was caught by Virat Kohli near the boundary off Suresh Raina.
De Kock’s ton, which included one six and 17 fours, came after he scored 103 in the third ODI in Rajkot. His dismissal failed to faze du Plessis, who then combined with captain AB de Villiers to make the most of a lacklustre and extremely generous Indian bowling display during the day-night match.
Right-hander du Plessis and his skipper took it in turns to smash sixes all over the ground.
Du Plessis hit six sixes and nine fours, even reaching a couple of boundaries while hobbling on one leg, and could have had many more if he had not been forced to retire with cramp.
De Villiers, 31, was a man on a mission, racing to 119 off only 61 balls, for his third century of the series.
He hit three fours and an astonishing 11 sixes before being caught behind by Mahendra Singh Dhoni off Bhuvneshwar Kumar.
India’s bowling figures made grim reading, with Kumar giving away 106 runs for just one wicket and Sharma conceding 84 for his one.
The hosts needed a miracle with the bat, but got off to the worst possible start when opener Rohit Sharma was caught on 16 and Kohli went for only seven.
Shikhar Dawan and Ajinkya Rahane put on a spirited show under the floodlights, notching 60 and 87 respectively, but South Africa’s total was never in danger.
Pacemen Kagiso Rabada and Dale Steyn were the stars of South Africa’s bowling attack, claiming four wickets and three wickets, respectively.
The one-day series will be followed by four Test matches. South Africa will be seeking a clean sweep, having won the earlier Twenty20 series 2-0.
The 2018 Boao Forum for Asia (BFA) annual conference is scheduled for April 8 to 11 in Boao, Hainan Province. The forum will be themed "An Open and Innovative Asia for a World of Greater Prosperity."
— The Daily Mail - People's Daily