Tristan Stubbs made 94 as South Africa declared their second innings on 260-5 to set India a record victory target of 549 and close in on a series win in the second Test on Tuesday.
World Test champions South Africa lead the two-match series 1-0 and even a draw in Guwahati would seal their first series win in India since 2000.
India suffered their fourth defeat in six home Tests in the opener in Kolkata and the hosts need to bat for more than three sessions to avoid another loss.
The highest successful run chase in Test cricket was West Indies' 418 against Australia in 2003. India's highest was 406 against West Indies in 1976.