The left-hander bludgeoned the ball all round the ground to record the joint second fastest fifty in Twenty20 international history, finishing with 77 from 31 deliveries as the touring side reached their target of 166 with four balls to spare.
Gayle was out trying to reverse-sweep leg-spinner Imran Tahir before leaving the ground with the score on 114 in under 11 overs to a standing ovation.
After South Africa had won the toss, they posted a competitive score of 165 for four but found Gayle in no mood to deal in singles.
The 35-year-old, who now holds the record for the fastest Twenty20 half-century for the West Indies after shaving three balls off the previous best by Kieron Pollard, bludgeoned five fours and eight massive sixes.
Marlon Samuels compiled a fluent 41 from 32 balls before he became the third wicket of the innings for the impressive Tahir, who conceded only 28 runs in his four overs.
South Africa’s total was built around an unbeaten 51 from 40 balls by left-hander Rilee Rossouw and captain Faf du Plessis struck a brisk 38 from 20 balls.
The second Twenty20 will be played in Johannesburg on Sunday before the final match in Durban on Wednesday. (Reuters)