Stuart Broad inspired England to only their third 10-wicket victory in one-day international history at Trent Bridge.
All-rounder Broad claimed career-best figures of five for 23 as South Africa were blitzed for just 83.
Kevin Pietersen's England team then raced into a 2-0 lead in the NatWest Series as openers Matt Prior and Ian Bell required just 14.1 overs to rubber-stamp the victory.
South Africa's paltry score was their second lowest in limited-overs internationals and scuppers their bid to return to the number one spot in the official rankings.
England have previously won just twice without losing a wicket chasing - against West Indies and Bangladesh at home in the past eight years.