De Villiers and Amla made England’s total of 171 look puny as they thrashed 125 runs in a 55-ball opening stand.
De Villiers, on the ground on which he hit the world’s fastest one-day international century against the West Indies last season, thrashed 79 off 29 balls with six fours and six sixes.
On the way he reached his fifty off 21 balls, the fastest for South Africa.
Amla was slightly more restrained but played some powerful strokes in making 69 not out off 38 balls with eight fours and three sixes.
The ease of South Africa’s win, which completed a 2-0 series victory, did not look a possibility while England captain Eoin Morgan and Jos Buttler were pounding sixes in a fourth wicket stand of 96 off 55 balls.
England had reached 157 for three and seemed set for a total well in excess of 200.
But Buttler (54) and Morgan were out off successive balls and England lost their last seven wickets for 14 runs after they had looked set to post a total in excess of 200.
South African captain Faf du Plessis said he was pleased with the win but felt his team had only produced a “70 percent” performance with the ball.
“Unlike (the first game at) Newlands we started well with the ball,” said Du Plessis.
“The first three overs were excellent but then it got away from us a bit. But we pulled it back and that’s important.”
Du Plessis said there was room for improvement but South Africa would be confident going into the World Twenty20.
De Villiers said he was happy to be opening the batting in 20 overs cricket.
“I’ll have to keep performing but I’ll open for as long as they want me to.”
Morgan, who was unlucky to be run out for 38 when bowler Kyle Abbott deflected a powerful drive from Ben Stokes into the stumps, said the collapse was “disappointing”.
But he was even more disappointed with England’s bowling.
“We started terribly with the ball,” he said.
“We missed our lengths and allowed them to play their natural game. When batsmen like that are in they will punish you.”
Morgan said, though, that he felt England could do well at the World Twenty20 in India next month.
“We are lacking experience but we have talent and I honestly think we are on the right track to win an ICC event.”
England’s collapse started when Buttler hit the third ball of the 17th over from Abbott into the covers where Du Plessis held a low catch, which had to be confirmed by the television umpire.
Buttler made 54 off 28 balls with four fours and four sixes.
Wickets tumbled, with Abbott finishing with three for 26. Chris Morris picked up two and Kagiso Rabada finished off the innings.
It was the last match of a tour during which England won a four-match Test series 2-1 and South Africa won a five-match one-day international series 3-2.