Put to bat first, Samson smashed 107 off 50 deliveries, hitting 10 sixes and seven fours to steer the Men in Blue to 202/8.
The spin-bowling duo of Varun Chakaravarthy (3/25) and Ravi Bishnoi (3/28) wrecked havoc on the Protea batting unit, restricting them to 141 under 18 overs.
Samson also became the first Indian to notch consecutive tons in T20Is, bringing up the three-figure mark in just 47 deliveries. He had pulled off similar heroics against Bangladesh last month.
:Samson smashes second straight T20I ton in superb batting effort against South Africa
However, South Africa clawed their way back into the game as they stemmed the flow of runs by picking wickets in the last five overs.
Pacer Gerald Coetzee who claimed three wickets was the pick of the bowlers for the hosts.
In reply, it was Varun (3/25 in 4 overs), who literally killed the contest by getting Heinrich Klaasen (25 off 22 balls) and David Miller (18 off 22 balls) in a space of three deliveries in the 12th over with South Africa being shot out for 141 in 17.5 overs.
But no praise is enough for Bishnoi (3/28 in 4 overs), who delivered a brilliant spell of 3/28 in 4 overs. In the 11th over, he bowled five consecutive dot balls to Miller, leaving the South African batter struggling to read his googlies as pressure mounted on the Proteas which was expertly capitalized on by Varun.
Brief Scores: India 202 for 8 in 20 overs (Sanju Samson 107, Tilak Verma 33; Gerald Coetzee 3/37) South Africa: 141 all out in 17.5 overs (Heinrich Klaasen 25; Varun Chakaravarthy 3/25, Ravi Bishnoi 3/28)