Just five of the fifteen selected played against the Boks the last time the sides met.
Robbie Henshaw will be starting at inside centre for Ireland against the World Champions on Saturday.
Conor Murray is set to earn his 100th Irish cap when he starts against South Africa at scrum-half with Jamison Gibson-Park named on the bench.
Murray is just one of just five players in the starting team that started the last game between the two sides in 2017.
Tadhg Furlong, Henshaw, Peter O’Mahony and Johnny Sexton were the other players to start against the Springboks five years ago.
Robert Baloucoune will line out on the wing while Garry Ringrose is set to start at outside centre.
The game at the Aviva Stadium will be Enniskillen native Baloucoune's third appearance in a senior Irish shirt.
37-year-old Johnny Sexton will captain Andy Farrell's side.
Former Ireland head coach and current Buccaneers boss, Eddie O'Sullivan says if Ireland can get the win against South Africa, they should win all their November series games.
James Gormley Named On Irish Squad For FIBA EuroBasket Qualifiers
Portlaoise Panthers Suffer Tough Defeat In Super League
CCFL: St Peter's Extend Their Advantage At Top Of Premier Division
NFL: Relegation Firmly On The Cards For Offaly
Laois "Devastated" By Defeat Despite Delivering "Manliness" - Justin McNulty
Westmeath Ladies Bag First Win Of League Season
Big Camogie Wins for Westmeath and Laois Over The Weekend
Fitzgerald "Relieved" After Squeaking Past Kerry
NHL: Galway Prove Too Strong For Offaly
Former Laois And Offaly GAA Manager Honoured By An Garda Síochána
Athlone Town Make It Two Wins From Two In First Division
Lee Fitzpatrick Scores Try For Ireland U20s In England
NFL: Westmeath Move Closer To Promotion
Shane Lowry Finishes Strong In California
Westmeath Drifter Sets Sights On Success In 2026
Offaly’s Alex Dunne Joins Alpine’s Young Driver Programme
NHL: Laois And Kerry Clash In Division Two
Shane Lowry Cards Opening Round 73 At Genesis Invitational
Athlone Town Aiming For Back To Back League Wins