Hashim Amla's 150 saw him become the fastest player to 3,000 ODI runs as he reached the landmark in just his 57th innings compared to the 69 it took West Indies great Vivian Richards.
It was also the highest individual score in ODI matches between South Africa and England, and the cornerstone of the Proteas' 287 for five, made after captain AB de Villiers won the toss.
England, in reply, were dismissed for 207 with more than nine overs left.
Amla's tenth hundred at this level surpassed team-mate Graeme Smith's 141 in Centurion three years ago as the largest solo effort in South Africa-England one-dayers and was also Amla's personal best, overtaking the 140 he made against Bangladesh in Benoni in 2008.
Victory saw South Africa take a 1-0 lead in this five-match series following Friday's washout in Cardiff and ended England's run of 10 straight wins in completed ODIs.
It also meant South Africa, having already dethroned England at the top of the world Test rankings this tour, also replaced them at the head of the equivalent one-day standings and were now top in all three formats.
South Africa only need to draw this series to cement their new-found status, while England must win it to remain in pole position in the 50-over game.
England's attack must be sick of the sight of Amla, who made a South Africa record 311 not out in the first Test at The Oval last month and another hundred as the Proteas sealed the three-match series 2-0 with victory at Lord's.
Opener Amla, a touch batsman rather than a power player, was in sight of the rare distinction of carrying his bat in a one-day match when, two balls before the end of the innings, he uppercut fast bowler Steven Finn to Tim Bresnan.
The ball before the elegant Amla, who put on 89 for the first wicket with Test skipper Smith (52), gave himself room to work the ball down to third man for a four that took him to 150 in front of a near-capacity Ageas Bowl crowd in this day/night fixture.
Amla faced 124 balls with 16 boundaries but was missed on 92 when Johannesburg-born wicket-keeper Craig Kieswetter failed to hold a difficult but catchable legside chance off Finn.
"Things are falling into place and an element of fortune has to go your way too," Amla told the BBC. "The one-day game has its own characteristics, up front it was difficult because the ball did (move) a bit."
De Villiers added: "Amla is on fire at the moment and breaking lots of records. As a team we are very proud of him.
"I hope he can continue like this for many years to come. We are proud to be number one in the world and we are working towards an ultimate goal of winning the World Cup."
England were reduced to nought for one when captain Alastair Cook was superbly yorked by Lonwabo Tsotsobe off just the second ball of their innings.
"We just didn't play well in all three areas, but credit to Hashim Amla," said Cook. "His innings showed us how to play."
Ian Bell got England going again but a second-wicket partnership worth 64 ended when Jonathan Trott, a former South Africa youth international, was brilliantly caught over his shoulder by Dean Elgar at long leg off Morne Morkel.
And 64 for two became 77 for three when Bell, whose 45 came at better than a run-a-ball, played down the wrong line to Robin Peterson.
Left-arm spinner Peterson then made it two wickets for three runs in eight balls when Ravi Bopara struck a long hop to short extra-cover.
England, without the exiled Kevin Pietersen, were now 90 for four.
Any hopes of a late England rally disappeared when Eoin Morgan, Bresnan and Swann all exited on the same total to leave the hosts 159 for eight.
Last man Finn and Patel entertained the crowd with some bold boundary hitting before Patel was caught behind for 45 off Morkel to end the match.
The series continues at The Oval on Friday.