Chasing 290 for victory, India were never in the hunt after they lost their first four batsmen for just 43 runs and were ultimately bundled out for 154 in 35.4 overs.
Virat Kohli top-scored for India with a well-made 54 off 70 balls and together with skipper Mahendra Singh Dhoni (25 off 35) added 52 runs for the fifth wicket to take India past the 150-mark.
Apart from Kohli and Dhoni, Suresh Raina was the other notable contributory for India with 32 off 36 balls.
Lonwabo Tsotsobe was the pick of the South African bowlers with figures of four for 31 while pace partners Dale Steyn (2/29) and Morne Morkel (2/12) scalped two wickets apiece.
Image: South Africa's bowler Lonwabo Tsotsobe, center, celebrates with teammates after taking a wicket of India's batsman Sachin Tendulkar, unseen, during the first One Day International cricket match against South Africa at the Kingsmead stadium in Durban, South Africa on Wednesday Jan. 12, 2011.
Scorecard | India vs South Africa