Tendulkar finished on 200 not out in eclipsing the previous highest score of 194, jointly made by Zimbabwe's Charles Coventry against Bangladesh in Bulawayo last August and Pakistan's Saeed Anwar against India at Chennai in May 1997.
Tendulkar carried his bat through all 50 overs, reaching the landmark in the last over off 147 deliveries to help India amass 401-3 and win by 153 runs.
South Africa, which lost the first match by 1 run, was all out for 248 in the 43rd over despite a fighting unbeaten 114 by AB de Villiers.
The nearly 30,000 in the partisan crowd went delirious as Tendulkar surpassed the previous highest score in one-dayers with two off fast bowler Wayne Parnell behind short fine leg in the 46th over.
Tendulkar's previous best was 186 not out against New Zealand at Hyderabad in November 1999.
He saved his biggest reaction for becoming the first man to 200, with a single off Charl Langeveldt with three balls left. He took off his helmet, raised it and his bat and savored the prolonged standing ovation from the crowd and both teams.
The 36-year-old dedicated his latest achievement to the "people of India who have stood behind me for 20 years whatever be the ups and downs."
He said he enjoyed batting as the ball was coming nicely onto the bat.
"When I was on 175-plus and only 42 overs bowled, I thought there was a chance" to score a double century, he said.
"But I wasn't thinking of it. Only when I got close to it, I really thought there is an opportunity."
Asked whether bowlers could expect some respite after his two decades in the game, Tendulkar said: "I am enjoying my cricket. I have always played the way I felt the right way to play and always done what I felt was good for the team."
To another question how his body was coping, he said: "I feel good that I lasted for 50 overs. A good test of my fitness.
"I would like to bat another 50 overs at some stage and see that the fitness level doesn't drop."
Tendulkar plundered runs from the Proteas almost at will with some dazzling cover drives and pull shots. He'd pick up deliveries from outside the off stump and hit them over mid-on. He smashed 25 boundaries and three sixes.
South African captain Jacques Kallis lauded Tendulkar and lamented his side.
"It was a fantastic knock. He took advantage of conditions," Kallis said. "We lost wickets at crucial stages. We have to work on basics."
Tendulkar punished Parnell for two successive boundaries in the first over he faced, and cricket's greatest international runmaker brought up his 46th one-day century in 90 balls in the 28th over.
He was involved in a record 194-run second-wicket partnership for India with Dinesh Karthik, who scored 79 off 85 balls.
An aggressive 35-ball knock of 68 not out by captain Mahendra Singh Dhoni highlighted India's domination.
Virender Sehwag was dismissed in the fourth over as he slashed hard at a delivery from Parnell, trying to clear the third man boundary. He was caught by Dale Steyn for 9 at 25-1, bringing in Karthik to join Tendulkar.
India reached 100 in the 15th over, 200 in the 31st, and 300 in the 41st in posting the ninth highest total in one-day history.
South Africa faced other problems on the field as well. JP Duminy injured his left palm as he tried to stop a powerful drive from Tendulkar on the off side in the fourth over. He later went on to bowl with a bandaged palm and came in for punishment from Tendulkar and Karthik.
Langeveldt also was hit by the ball and suffered a cut above his left eye, but he continued to bowl as runs rained from the blade of Tendulkar.
Parnell claimed 2-95, but the least expensive bowler was Roelof van der Merwe with 1-62 in his 10 overs.
A rattled Proteas couldn't take up the Indian challenge as half of the side was back in the dressing room for 102 in 14 overs.
The only redeeming feature was de Villiers who, even as wickets kept falling at the other end, notched his fifth one-day hundred off 85 deliveries, including 13 boundaries and two sixes.
Opener Herschelle Gibbs, South Africa's key player in the chase of 434 against Australia in 2006, disappointed as he attempted to play fine an outside off stump delivery from medium-pacer Parveen Kumar, got an inside edge and was bowled for 7.
Hashim Amla, inducted into the side after he scored more than 400 runs in the test series against India, was again on a roll. He hit India pace bowler Ashish Nehra for four boundaries, three of them consecutively, in the fourth over.
However, Amla, too, could not build on a good start and his departure triggered a collapse.
Nehra had reasons to smile as he caught Amla at mid-on after the latter pulled a short pitched delivery from pacer Shanthakumaran Sreesanth from outside the off stump. Amla scored 34 off 22 balls, including seven boundaries. Nehra then bowled Kallis for 11 at 83-4.
At 103-6 runs in the 15th over, de Villiers and Mark Boucher tried to repair the damage.
However, it was India's day and it bowled out the visitors in 42.5 overs. Sreesanth bagged 3-49, Nehra 2-60 and Yusuf Pathan 2-37.
The third match is on Saturday at Ahmedabad.
