Sandun Weerakkody is likely to be given another chance despite his failure in his debut in the first game of the ongoing five-match series.
In that game, Weerakkody opened batting with Niroshan Dickwella.
However, all three are lacking in experience to play a longer innings, which is prompting Tharanga to be promoted in the batting order.
He is the most experienced player in the side with 194 games under his belt, of which he opened batting on 151 occasions.
As an opener, Tharanga scored 4,902 runs with 13 centuries and 25 half centuries.
In the other 43 games, he collected only 725 runs with five half centuries.
South Africa is likely to field an unchanged side from their first match win.
This will be the last ODI series for Sri Lanka against a strong team, although they host Bangladesh in a three-match series before the Champions Trophy in June.