Pietersen and Andrew Flintoff, who made 78 from 70 balls, hauled England up from 113-3 after 30 overs to 275-4 from 50 with a stand of 158 for the fourth wicket - a record for 50-over internationals on this ground.
And Pietersen's Midas touch returned in the South African innings when four bowling changes - Steve Harmison (twice), Samit Patel and the captain himself - produced wickets in their first over as the tourists were all out for 255.
Pietersen ended with figures of 2-22 with his off-spin and Harmison 2-43 whilst Flintoff knocked over the tail.
Pietersen said: "The last time Andrew Fintoff batted like that with me was at Edgbaston against Australia in 2005. We gave him a new role at number five. The man is a superstar - I am fortunate to have a bloke like that who I can throw the ball to say knock over the stumps.'
"We asked a lot of the players but we won't be resting on our laurels. The team were brilliant - we started off well and built a good foundation.
"And this is the stage where Steve Harmison belongs. He should be playing in front of 30,000, 40,000, 50,000."
South African captain Graeme Smith added: "We know they can hit the ball but if we get our execution right we should never be going for 98 in the last ten. There is a feeling in the dressing room we can do a lot better.
"We pride ourselves on being better than that. But England deserved their win - they played with a lot more skill."
In contrast to England, South Africa set off at pace in pursuit of their target with Herschelle Gibbs and Graeme Smith taking the score to 50 before Pietersen called up Harmison for his first one-day international bowl for nearly two years.
Four balls later the Durham quick had Smith caught behind and Gibbs was then bowled by Patel to leave South Africa 93-2 in the 15th over. And a steady flow of wickets saw England to victory.
It was with the bat that Pietersen made his most telling contribution. After playing themselves in carefully, Flintoff and Pietersen unleashed a torrent of boundaries to demolarise the South Africans.
For Flintoff, it was his highest score in one-day internationals since 2005 and he hit nine fours before being bowled backing away by Sale Steyn in the final over.
Pietersen escaped two big leg before appeals and a close run out when his bat appeared to bounce over the crease when he was on 23 and took 52 balls to hit his first four.
But once he had found his range Pietersen and Flintoff took the score from 150 to 200 in just 38 balls before accelerating once more towards the end of the innings.