The pressure in the chase then proved simply too much for South Africa on Friday as they slumped to 148 all out with 10 balls left, leaving India to celebrate a 135-run victory.
Six bowlers took wickets for India, led by medium-pacer Arshdeep Singh's 3-20 in 15 deliveries, as the visitors completed a 3-1 series win.
It was man-of-the-match and series Varma and Samson who stole the show at the Wanderers.
Tilak Varma was named player of the match and series. (AP PHOTO)
Varma top-scored with 120 not out off 47 balls to make him only the second India batter after Samson to score back-to-back T20 centuries, and only the fifth batter ever.
Samson himself scored 109 not out off 56 balls, his second century of the series and third in five T20 innings.Â
He became the first batter to score three T20 centuries in a calendar year, and the second batter to notch two hundreds in the same bilateral tournament.
Together, they blasted 210 runs off 86 balls for the second wicket, hitting 19 sixes and 15 boundaries.
Theirs was the highest T20 partnership for India for any wicket. It was also the highest T20 partnership against South Africa, and the highest for the second wicket or lower in all T20s.
Sanju Samson has become the first batsman to score three T20 centuries in a calendar year. (AP PHOTO)
After India chose to bat first, Samson and Abhishek Sharma opened with 73 off 35 balls, setting the stage.
Sharma was dropped before he scored but went on to make 36 off 18 balls, including four sixes, before falling to Lutho Sipamla - the lone wicket of the innings.
Samson motored on, reaching 50 off 28 balls with five fours and three sixes. He accelerated to his hundred off 51 balls - the second 50 coming off 23 balls with another five sixes and three fours.
Only Rohit Sharma (five) and Suryakumar Yadav (four) now have more T20 hundreds for India.
Varma wasn't shaded. He raced to 50 off 22 balls with five sixes and four fours, and the next 50 came off 19 balls with four more sixes.
The duo racked up a 100 partnership off 40 balls, and doubled it in another 42 deliveries.
It was the third time two batters scored individual hundreds in the same T20 innings and the first instance between full-member sides.
It was also the second highest T20 total between full-member sides - India scored the highest (6-297) against Bangladesh in Hyderabad last month - when Samson posted the first of his three centuries.
Singh then quickly gave South Africa no hope in the chase, bowling Reeza Hendricks for a two-ball duck, while skipper Aiden Markram was out caught for eight.
Hardik Pandya sent back Ryan Rickelton for one, and South Africa were down to 4-10 in just three overs when Singh dismissed Heinrich Klaasen lbw for a golden duck.
Tristan Stubbs and David Miller (36) resisted with an 86-run partnership off 54 balls, but it was never going to be enough. Stubbs top-scored with 43 off 29 balls.
Marco Jansen provided a late flourish with 29 not out off 12 balls, as mystery spinner Varun Chakravarthy recorded figures of 2-42, finishing with 12 wickets in the four-match series.
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