The classy batsman hit six fours and four sixes in his 44-ball knock as England finished on 230-8 with two balls to spare after South Africa made 229-4.
It was the highest successful chase in the Twenty20 World Cup and the second highest successful run chase by any team in the history of the shortest format of the game.
Moeen Ali dramatically hit the winning run after England went into the last over needing just one run to clinch victory.
Opener Jason Roy had earlier scored 43 while Jos Buttler made 21.
Left-handed de Kock reached his 50 off just 21 balls thanks to seven fours and three sixes that included a beautiful array of shot-making in the Super 10 Group one game.
England skipper Eoin Morgan experimented with six different bowlers in the first seven overs as de Kock and Amla made easy work of David Willey and Reece Topley, among others, to reach 96-0.
England finally made a breakthrough in the eighth over when de Kock, on 52, was caught deep by Alex Hales off spinner Moeen Ali, providing them a rare moment of joy.
The two quick wickets helped to stem the South African tide momentarily and gave England a brief moment of hope, however South Africa’s strength in depth shone through.
England were left to rue a simple dropped catch by Topley in the fourth over that would have seen Amla walk as the batsman went on to notch his half-century in the tenth.
He was eventually out leg before wicket by Ali in the 12th over on 58.
Proteas skipper Faf du Plessis came in at number four and made 17 while Duminy expertly took over where de Kock and Amla had left off.
The left-hander, batting at number five, scored 54 not out that included three sixes and three fours.