Find out all you need to know about the clash between the sides at Mohali
Both teams begin their preparations in earnest for next year's World T20 with three 20-over matches in the space of a week. The fixtures come ahead of a three-Test series between the two nations in October.
While India dominated the multi-format tour of the West Indies, South Africa have not played any competitive international cricket since the 50-over World Cup, when they crashed out in the group stage.
The first scheduled T20 between the nations on Sunday in Dharamsala was rained off without a ball being bowled.
FIRST T20: Himachal Pradesh Cricket Association Stadium, Dharamsala (Sunday, September 15) - Match abandoned
SECOND T20: Punjab Cricket Association Stadium, Mohali (Wednesday, September 18)
THIRD T20: M.Chinnaswarmy Stadium, Bangalore (Sunday, September 22)
A washed-out opening T20 means this match represents India's first outing since they swept aside the West Indies in emphatic fashion.
Virat Kohli's men were ruthless, with only rain denying them a clean sweep of the Test, ODI and T20 series contested between the two sides.
The Windies offered little resistance in the 20-over matches. They were unable to score more 146 in any single innings and twice failed to reach three figures.
Though a number of leading figures were rested, India cruised to a 3-0 series win. While Rohit Sharma and was in among the runs, debutant Navdeep Saini starred with the ball.
The 26-year-old has retained his place for this series and it will be intriguing to learn how he copes with an improved standard of opponent.
Indeed, South Africa, though themselves going through a transition, are expected to pose a greater challenge to India than the West Indies did last month.
India are the favourites, with Dafabet offering odds of 3/4 for the hosts to prevail. South Africa are available at 11/10.
Hardik Pandya is the big name who returns to the T20 squad after being rested for the West Indies tour. He replaces Bhuvneshwar Kumar in the only change from the group.
MS Dhoni, whose international future remains unknown, and Jasprit Bumrah will not be part of the series. Kuldeep Yadav and Yuzvendra Chahal also remain out of the fold.
India squad: Virat Kohli (c), Rohit Sharma, KL Rahul, Shikhar Dhawan, Shreyas Iyer, Manish Pandey, Rishabh Pant (wicketkeeper), Hardik Pandya, Ravindra Jadeja, Krunal Pandya, Washington Sundar, Rahul Chahar, Khaleel Ahmed, Deepak Chahar, Navdeep Saini
With Faf du Plessis choosing to play for Kent in the County Championship in preparation for the Test series, Quinton de Kock will captain The Proteas in the T20s. There are also three new faces in the form of Temba Bavuma, Bjorn Fortuin and Anrich Nortje.
Chris Morris was not considered for selection, with trio Aiden Markram, Theunis de Bruyn and Lungi Ngidi also overlooked as they play for South Africa A ahead of the Test series.
South Africa squad: Quinton de Kock (c), Rassie van der Dussen (vc), Temba Bavuma, Junior Dala, Bjorn Fortuin, Beuran Hendricks, Reeza Hendricks, David Miller, Anrich Nortje, Andile Phehlukwayo, Dwaine Pretorius, Kagiso Rabada, Tabraiz Shamsi, Jon-Jon Smuts
Any rain expected in Mohali on Wednesday is expected to have cleared by the time play is scheduled to start, which should lead to a full game.
Star Sports are scheduled to show the series in India, while Supersport will provide coverage from South Africa. No UK broadcaster is confirmed to broadcast matches during the series.
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