Sexton has been named ahead of veteran Munster playmaker Ronan O'Gara who had been the heavy favourite to win his 94th cap.
Head coach Declan Kidney has given his backing to 24-year-old Sexton after the youngster produced a man-of-the-match display against Fiji last Friday.
Sexton was highly praised by both the Irish and Fijian coaching staff after he guided Ireland to a comprehensive 41-6 victory and finished with a 100-per-cent kicking record on his international debut.
O'Gara, who was part of Munster's Magners League winning side last season, has been undoubted first-choice for his country since the retirement of Ulster legend David Humphreys five years ago.
But Kidney has decided to drop one of the heroes of Ireland's Grand Slam triumph in favour of the man many Irishmen are tipping as the central figure in the future of international rugby in the Emerald Isle.
Elsewhere, in the Ireland starting XV, Kidney makes six changes from the side that started the clash with Fiji at the RDS.
Leinster prop Cian Healy returns to the front row, with Munstermen David Wallace, Donncha O'Callaghan and Tomas O'Leary joining Ospreys wing Tommy Bowe and Ulster centre Paddy Wallace in returning to the first XV.
There was also good news for Munster supporters after back row Denis Leamy was named among the replacements for the final match of Ireland's autumn series.
It had been feared that Leamy would miss Saturday's game, plus Munster's Magners League tie with the Ospreys in early December, after he was carried off injured on Friday night.
Ireland (vs South Africa, Saturday, November 28, Croke Park, kick off 2.30pm)
Rob Kearney (Leinster), Tommy Bowe (Ospreys), Brian O'Driscoll (Leinster, captain), Paddy Wallace (Ulster), Keith Earls (Munster), Jonathan Sexton (Leinster), Tomas O'Leary (Munster); Cian Healy (Leinster), Jerry Flannery (Munster), John Hayes (Munster), Donncha O'Callaghan (Munster), Paul O'Connell (Munster), Stephen Ferris (Ulster), David Wallace (Munster), Jamie Heaslip (Leinster)
Replacements: Sean Cronin (Connacht), Tony Buckley (Munster), Leo Cullen (Leinster), Denis Leamy (Munster), Peter Stringer (Munster), Ronan O'Gara (Munster), Gordon D'Arcy (Leinster)
Guinness PRO12
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