Opting to bat, India notched up 289 for seven in the allotted 50 overs and in reply, South Africa were 43 for one in 7.2 overs when play was stopped at the Wanderers.
Hashim Amla was batting on 19 while his opening partner and skipper Aiden Markram was dismissed by Jasprit Bumrah for 22.
South Africa required another 247 runs with nine wickets and 42.4 overs remaining.
Earlier, India were 200 for two in 34.2 overs when the umpires called for the covers. Shikhar Dhawan was batting on 107 off 102 balls then.