Opener Tazmin Brits (81; 56b) and Marizanne Kapp (57; 33b) struck belligerent fifties as South Africa posted an imposing 189/4 after India opted to bowl.
In reply, Smriti Mandhana (46; 30b) and Shafali Verma (18; 14b) gave India a brisk start before South Africa triggered the collapse.
Jemimah Rodrigues raised India's hopes lower down the order with 53 not out from 30 balls, while Harmanpreet Kaur made 35. But South Africa held nerves to restrict them to 177/4.
Earlier, Brits slammed three sixes and 10 fours in her career-best knock of 81. Kapp hit eight fours and one as the duo stitched 96-run partnership from 56 balls.
Skipper Laura Wolvaardt made 33 from 22 balls and Brits raced to 50 runs in 43 balls for the opening wicket before Radha Yadav (2/40) gave India the first breakthrough.
Pooja Vastrakar was the pick of Indian bowling with her 2 for 23.
The second and third T20Is are slated here on Sunday and Tuesday.
India had defeated South Africa in the one-off Test before sweeping the ODI series 3-0.
Brief Scores:
South Africa (189/4 in 20 overs (Tazmin Brits 81, Marizanne Kapp 57; Pooja Vastrakar 2/23, Radha Yadav 2/40)) bt India (177/4 in 20 overs (Jemimah Rodrigues 53, Smriti Mandhana 47)) by 12 runs.