The left-handed Rossouw made an unbeaten 100 in 48 balls to steer South Africa to 227-3 after being invited to bat first in Indore.
South African bowlers then combined to bowl out India for 178 in 18.3 overs, but the hosts took the three-match series 2-1 — their first ever against the Proteas at home — after winning the first two matches.
It was the last match for both the teams ahead of the T20 World Cup in Australia starting later this month and the 32-year-old Rossouw made it count for the tourists.
Quinton de Kock, who hit sixty-eight off forty-three balls, and Rossouw put on eighty-nine for the second wicket after skipper Temba Bavuma, who got ducks in the two losses, fell to three.
Rossouw survived a dropped catch on twenty-four by Mohammed Siraj in the deep as the ball popped out of his hands for a six. De Kock made his second successive fifty with a hit over the fence off Umesh Yadav.
The pair hit eight sixes between them before the partnership ended with De Kock’s run out in his attempt to steal a second run.
Rossouw, who hit eight sixes, then got going with Tristan Stubbs in another big partnership of eighty-seven and surpassed his previous best of ninety-six not out to reach his hundred in forty-eight balls.
Stubbs, who was warned by pace bowler Deepak Chahar for backing up too far at the non-striker’s end when on thirteen, made twenty-three.
Rossouw finished unbeaten and David Miller, who hit a one hundred in the second T20, smacked three straight sixes in the final over from Chahar to score an unbeaten nineteen off five balls.
In reply, India lost two early wickets including skipper Rohit Sharma for a duck after the opener got an inside edge on to his stumps from pace bowler Kagiso Rabada.
Wicketkeeper-batsman Rishabh Pant (27) and Dinesh Karthik (46) attempted to revive the chase in an attacking partnership of forty-one off twenty balls.
The left-handed Pant got out after hitting three fours and two sixes in his 14-ball knock, but Karthik kept up the charge.
Left-arm spinner Keshav Maharaj denied Karthik his fifty after the batsman attempted a reverse scoop only to be bowled.
The rest of the batting, which missed Virat Kohli and KL Rahul who were rested, failed to challenge the bowlers apart from Chahar who made a valiant 31 of 17 balls.
Fast bowler Dwaine Pretorius, who came in for the rested Anrich Nortje, stood out with figures of 3-26 in his 3.3 overs.
