Playing without key openers Gautam Gambhir and Virender Sehwag, India rode on a brilliant half-century by Rohit Sharma (53 off 34 balls) and Suresh Raina's racy 23-ball 41 to post a competitive 168/6 after skipper Mahendra Singh Dhoni won the toss and elected to bat.
The visitors then returned to restrict South Africa to 147/9 in the stipulated 20 overs to complete the victory at the Moses Mabhida Stadium.
Ashish Nehra and Yusuf Pathan chimed in with two wickets each to contribute to the cause.
For South Africa, opener Morne van Wyk blasted a whirlwind 39-ball 67 comprising five fours and as many sixes but he didn't get support from the other end as the hosts fell short by 21 runs in the end.
India and South Africa will next play the five-match one-day series starting on Wednesday.
In Image: India's captain Mahendra Singh Dhoni holds the trophy after winning their Twenty20 cricket match against South Africa at the Moses Mabhida stadium in Durban, South Africa on Sunday Jan. 9, 2011. India won by 21 runs.