India chose to field in Sunday's final ODI, and bowled out South Africa for 287 on the penultimate ball of the innings.
Yet the visitors narrowly failed in their chase as their last wicket fell on 283, with four balls still left in the innings.
Deepak Chahar scored a fine 54 from 33 balls to get India close, but they lost their last three wickets for the addition of five runs as the home side bundled out the lower order.
De Kock's 17th ODI century boosted South Africa's total, his 124 coming from 130 balls as he added 134 for the fourth wicket with Rassie van der Dussen, who made a solid 52 from 59 balls.
David Miller weighed in with 39 at the end of the innings, but South Africa may have felt they were 30 runs short, having been 3-214 in the 36th over. Prasidh Krishna was the pick of the visiting attack with 3-59.
India were on course in their chase when they reached 1-116 in the 23rd over, but two quick wickets proved a massive setback.
Shikhar Dhawan (61) skied a pull shot to wicketkeeper De Kock off seamer Andile Phehlukwayo (2-38) and, off his first ball, the dangerous Rishabh Pant tried to launch the same bowler for six but was caught at deep cover.
It was poor shot selection from Pant, not for the first time on the tour.
When former captain Virat Kohli (65) departed, only the lively 54 from Chahar got India within touching distance.
Seamers Lungi Ngidi (3-58) and Phehlukwayo (3-40) again impressed for the hosts as South Africa continued where they left off in the Test series, which they won 2-1.
