Robin Petersen himself scored 62 runs, but deemed that Jacques Kallis' unbeaten knock of 78 as more important in placing the Proteas just 35 runs behind the visitors at close of play.
Faf du Plessis and AB de Villiers produced 205 runs for the fifth wicket but South Africa failed to complete a historic run chase in Johannesburg.
South Africa will have to either see out 90 overs for a draw or chase down 320 runs for victory. While the former looks the more likely option for the hosts, the odds remain on India to go 1-0 up in the two-match series.
India took complete control against South Africa (138/2 in second innings) on Day 4 with the hosts staring at a huge target on a challenging pitch.
Despite Dwayne Smith's heroics, the Mumbai Indians skipper believes that the bowlers played a key role in the victory.
Dwayne Smith slammed an unbeaten half-century while Kieron Pollard scored a quick-fire 31 to help Mumbai Indians register a comfortable victory and also stay in hunt for a semifinal spot.
Head selector Andrew Hudson says Petersen is "the obvious choice" to come in for former limited-overs captain Smith, who was ruled out of the ODI tournament to have surgery on his injured left ankle.
Smith was forced to watch South African team-mate Alviro Petersen hit 167 after losing the toss on the opening day of the English County Championship First Division clash 24 hours earlier.
South Africa tucked into some valuable batting practice ahead of next week's opening Test reaching 128 for one after the second day of their three-day tour match against Australia A at the Sydney Cricket Ground on Saturday.