Buttler joined forces with Somerset team-mate Craig Kieswetter, who topscored with 50, as the pair hit 50 off the final 15 deliveries to end on 118 for five off 11 overs after the match was reduced due to rain.
South Africa, having won the toss and elected to bowl first, could only muster 90 for five in response as the ever-prolific Hashim Amla (36) lacked support in the floodlit contest.
As a result of the comprehensive win, England tied the three-match series 1-1 with the second T20 at Old Trafford having been washed out.
England enjoyed a flying start courtesy of a wild opening over from Morne Morkel, who delivered one of the widest wides ever seen in international cricket and conceded 16 runs.
Michael Lumb got going with a driven four off the ineffectual Wayne Parnell, but the Nottinghamshire man, back after more than a year on the sidelines, was bowled by Parnell just two balls later looking for a repeat.
Kieswetter continued to find the ropes with regularity in what was a belligerent and effective knock, but Luke Wright departed for six after completely mis-hitting an off-break from Johan Botha to Hashim Amla at point.
Eoin Morgan was fortunate to survive an lbw appeal by Robin Peterson, and he was soon dismissed by Botha for five.
With two overs to go, England had just 74 on the board, but man-of-the-match Buttler set about thrilling the Birmingham crowd with some inventive and destructive hitting.
Parnell conceded a staggering 32 runs off one over, with Buttler hitting three sixes and two fours, and suddenly England were roaring past the 100 mark with South Africa reeling on the back foot.
Man-of-the-series Kieswetter's third six brought up his half-century, before Morne Morkel removed both him and Jonny Bairstow in the final over.
Buttler ended with an astonishing strike rate of 320, with South Africa requiring 119 runs to win from their 11 overs at well over 10 runs per over.
Richard Levi ended a disappointing series with a four-ball one as Tim Bresnan clean bowled him, but fellow opener Amla continued his fine form with six boundaries in another impressive innings.
Faf du Plessis was another South Africa batsman who did not manage to make an impact in the series, and he departed for just eight, as debutant spinner Danny Briggs took his first wicket with Morgan taking a comfortable catch in the deep.
The crucial wicket of AB de Villiers was next, as the South Africa skipper holed out to Bairstow at deep midwicket for just two. It was a huge blow for the tourists.
Amla could not build on his 36 as Graeme Swann had him caught on the midwicket boundary with Bairstow again the man to take the catch, and Justin Ontong was the final wicket to fall after he skewed a full delivery from Bresnan to Morgan at point.
Kallis was left unbeaten on eight, batting at number seven, alongside the big-hitting Albie Morkel, who had 17 to his name as the innings came to a close with the tourists well short of their target.
England will have been happy to end a gruelling international summer on a high, but the attention for both sides will now swiftly switch to the World Twenty20 as Andy Flower’s men bid to defend their title.