Having recorded a 141-run victory in Johannesburg on Thursday, the hosts once again proved far too strong in opening up an unassailable 2-0 lead with one match still to play.
South Africa were put into bat and racked up 280-6 in a game reduced to 49 overs a side, thanks largely to a first-wicket stand of 194 between De Kock and Amla.
The young wicketkeeper-batsman followed his 135 three days earlier by striking 106 from 118 balls, while Amla (100) became the fastest batsman to 4,000 ODI runs – beating Viv Richards by reaching the mark from 81 innings.
India never looked like pulling off a successful chase and soon subsided to 146 all out.
Lonwabo Tsotsobe led the way with the ball for South Africa, claiming 4-25, while fellow seamers Dale Steyn and Morne Morkel returned 3-17 and 2-34 respectively.
As had been the case in Johannesburg, De Kock and Amla gave their side another strong start.
Both brought up 57-ball fifties and emerging talent De Kock went on to reach three figures - for the third time in ODIs - in the 33rd over.
The left-hander's fine innings ended when he was caught at square-leg by Rohit Sharma off Ravichandran Ashwin, and captain AB de Villiers (three) was stumped off Ravindra Jadeja in the following over.
Mohammad Shami (3-48) enjoyed success in the closing stages of the innings, dismissing Amla, whose innings spanned 117 deliveries, David Miller (0) and Jacques Kallis (10) either side of JP Duminy (26) being run out.
Steyn then struck an early blow in India’s reply, ousting Shikhar Dhawan for a duck.
The dangerous Virat Kohli also went without scoring to Tsotsobe, who got rid of Rohit (19) before Morkel removed Ajinkya Rahane to leave India in deep trouble on 34-4.
Suresh Raina (36) and MS Dhoni (19) put on 40 for the fifth wicket, but the captain was caught behind off Vernon Philander (1-20) and Morkel accounted for Raina.
Steyn and Tsotsobe finished things off by sharing the final four wickets, with the latter seeing De Villiers pull off a fine catch on the boundary to account for Jadeja (26).