Tendulkar hit an unbeaten 200, the first ever double century in ODIs, and built partnerships with Dinesh Karthik (79), Yusuf Pathan (36) and Mahendra Singh Dhoni (68) as India finished with a mammoth total of 401 for three.
South Africa stuttered with their reply and although AB de Villiers made a brave 114, the visitors were bowled out for 248 in 42.5 overs.
India, with Tendulkar at the forefront, were merciless with the bat, despite the early loss of Virender Sehwag (nine), as they made the most of Dhoni's rare success with the toss.
Sehwag, pronounced fit only hours before the start following a back injury sustained in the previous game in Jaipur, was caught at third man off Wayne Parnell, but South Africa thereafter were battered into submission on a placid surface.
Tendulkar, who had lashed Parnell for boundaries on either side of the wicket for his first runs, unleashed an onslaught from which South Africa never recovered.
The master batsman brought a dazzling array of strokes into play as he smashed South Africa's bowlers around the park en route to a 37-delivery half-century.
He slowed down a bit as he neared his 46th ODI century, but once past the mark, he again opened up, smashing Jacques Kallis for three boundaries in one over.
Karthik, who had come in at the fall of Sehwag's wicket, had played the supporting role admirably as he went on to achieve to his fourth ODI half-century.
The pair added 194 for the second wicket when Parnell struck again, luring Karthik into a pull which the batsman mistimed, hitting straight to Herschelle Gibbs at mid-wicket.
There was little respite for South Africa, however, as Pathan smashed four boundaries and two sixes in a brief stay, while adding 81 for the third wicket.
Pathan's dismissal at the start of the 42nd over, however, hardly created a blip as Dhoni raised the tempo with a blistering innings, reaching his 35th half-century in the process.
Tendulkar, meanwhile, raised the highest individual score in one-day cricket, going past the previous mark of 194 jointly held by Pakistan's Saeed Anwar and Zimbabwe's Charles Coventry.
He reached the mark off only 140 deliveries with a couple of runs of Parnell, hitting 25 boundaries - the most by a batsman in a single innings - and three sixes along the way, before reaching his double century with a single off Charl Langeveldt in the final over.
South Africa, who hold the record for the world's highest chase in one-day internationals, began in poor fashion as they lost Gibbs (seven) in the third over and thereafter suffered blows regularly.
Gibbs attempted to paddle a delivery - pitched outside off - from Praveen Kumar to square leg, but only managed to drag the ball back onto his stumps.
Pinch-hitter Roelof van der Merwe (12) lasted only 12 deliveries, miscuing Shanthakumaran Sreesanth to Suresh Raina at cover, while Hashim Amla made 34 before he was Sreesanth's second victim.
Kallis had made 11 when he dragged a delivery from Ashish Nehra onto his stumps, Alviro Petersen was bowled by Ravindra Jadeja for 11 and JP Duminy was trapped in front for a first ball duck by Pathan.
The experienced pair of Mark Boucher and De Villiers then added 31 runs for the seventh wicket, but Pathan broke that stand by winning a lbw verdict against Boucher.
De Villiers then continued to offer stiff resistance and reached his fifth ODI century, but Nehra took a superb catch at mid-on to remove last-man Langeveldt (12) and bring up victory.
Jadeja and Sreesanth finished with three wickets apiece.
Highest individual scores in one-day international cricket:
1. 200 not out - Sachin Tendulkar, India vs. South Africa, Gwalior, Feb 2010
2. 194 not out - Charles Coventry, Zimbabwe vs. Bangladesh, Bulawayo, Aug 2009
3. 194 - Saeed Anwar, Pakistan vs. India, Chennai, May 1997
4. 189 not out - Viv Richards, West Indies vs. England, Manchester, May 1984
5. 189 - Sanath Jayasuriya, Sri Lanka vs. India, Sharjah, Oct 2000
6. 188 not out - Gary Kirsten, South Africa vs. United Arab Emirates, Rawalpindi, Feb 1996
7. 186 not out - Sachin Tendulkar, India vs. New Zealand, Hyderabad, Nov 1999
8. 183 not out - Mahendra Singh Dhoni, India vs. Sri Lanka, Jaipur, Oct 2005
9. 183 - Sourav Ganguly, India vs. Sri Lanka, Taunton, May 1999
10. 181 not out - Matthew Hayden, Australia vs. New Zealand, Hamilton, Feb 2007
11. 181 - Viv Richards, West Indies vs. Sri Lanka, Karachi, Oct 1987
