Quinton de Kock (101) and AB de Villiers (109) were the stars for the hosts as they both made centuries, with De Kock becoming the fifth batsman in history to notch 100s in three successive ODI innings.
The next-highest scorer was David Miller, who finished on 56 not out as South Africa reached 301-8 from their 50 overs.
De Kock's opening partner Hashim Amla (13) was the only other Protea to reach double figures.
Ishant Sharma was the pick of the bowlers for India with four wickets for 40 runs from his 10 overs.
South Africa have already won the three-game series thanks to convincing victories in Johannesburg and Durban.