Hashim Amla and Quinton de Kock got South Africa off to a steady start.
Hashim Amla became the fastest to 6,000 ODI runs but fell soon after, giving Mohit Sharma his wicket.
Despite the breakthrough, Quinton De Kock and Faf Du Plessis kept the scoring rate going with regular boundaries.
Faf du Plessis' sensational run of form and consistency continued as he followed up a series of fifties with a big century.
Quinton De Kock unleashed an array of breathtaking strokes enrolee his century as Indian bowlers were carted around by the opener.
Dale Steyn had Ajinkya Rahane caught at deep mid-wicket to trigger a middle-order collapse.
With his regular bowlers going for plenty, MS Dhoni resorted to the part-time bowling option of Virat Kohli
Kyle Abbott, picked ahead of Chris Morris, bowled steadily and accounted for the dangerous Rohit Sharma.
Ajinkya Rahane scored a brisk half-century to keep alive India's hopes of pulling off an improbable win.
Shikhar Dhawan and Ajinkya Rahane shared a solid partnership and raised India's hopes of taking the game close before Kagiso Rabada dismissed the former.
Soon after getting to his century, Faf du Plessis suffered a bout of cramp and had to retire hurt.
AB de Villiers received the ODI series trophy from BCCI Secretary, Anurag Thakur.
AB de Villiers became the third centurion of the South African innings and his blitz helped the visitors post a daunting 438.
South Africa completed an ODI series win in India for the first time.
Virat Kohli of India congratulates Faf du Plessis of South Africa on his innings as he retires with cramp