The match in Manchester was reduced to nine overs per side and South Africa were led by a spectacular 47 not out from Hashim Amla as they notched up 77 for five wickets.
Steven Finn took two for 17 from his two overs as the batsmen and fielding side struggled in the greasy conditions, Jacques Kallis (13 not out) helping to boost the score at the end with a seven-ball cameo.
The rain showed no sign of abating as England's batsmen took the field and they never got going, opener Craig Kieswetter swiping desperately at Morné Morkel's first over.
England were 29 for two off 4.1 overs when the umpires, aware that five balls were required to force a result under the Duckworth-Lewis method, called the players off the field.
South Africa won the first match on Saturday and can seal a series victory in the third game on Wednesday ahead of the September 18 to October 7 Twenty20 World Cup in Sri Lanka.
Stuart Broad will fly to Sri Lanka on Thursday for England's defence of their World Twenty20 title buoyed by the season-ending win.
Having lost the preceding Test series against the Proteas and been held to another drawn campaign in the one-dayers, all-rounder Broad was delighted to sign off the home season with a victory.
"To get on that flight with a win under our belt is brilliant," said Broad.
"It was awesome to see and a great confidence boost for the squad going to Sri Lanka … We've got eight of our  World Twenty20 winners here and guys who are performing now, so I'm really excited about getting on that flight … We have some talent in this changing room. It's important we believe we can do good things and we've got that belief now," added Broad, whose squad will be without Kevin Pietersen, man of the tournament when they won the 2010 World Twenty20 in the Caribbean, as the star batsman's England exile continues.
Buttler's international best performance effectively accounted for the victory margin with the Somerset batsman hitting three sixes and two fours.
The 22-year-old's deft use of the ramp shot and some powerful hitting was mainly responsible for South Africa left-arm quick Wayne Parnell conceding 32 runs in the ninth over – the second most expensive in Twenty20 internationals.
Broad, who holds the unwanted record after being smashed for six sixes by India's Yuvraj Singh in an over costing 36 runs in 2007, was glad to see Buttler at last replicate his county form for England.
"We knew we had hitters to come in and Jos played a game-changing innings," said Broad.
"We've seen this fella do it for Somerset time and time again, so to see him do it in an England shirt was brilliant," the seam bowler added.
"We look for guys who can change the momentum of games and Jos really did win us the game … Going into the final three overs it looked like we needed a push and Jos got 32 in 10 balls. That would change most games."
South Africa captain AB de Villiers, who as a wicket-keeper had a good view, paid tribute to man-of-the-match Buttler by saying: "You have to give credit where it's due and he certainly took it to us.
"I thought he hit a few very inventive shots and that's what's needed in this format." – Reuters, AFP