Jared Payne has been ruled out of the Ireland team to face South Africa on Saturday after failing to overcome a calf injury, while CJ Stander returns from suspension.
Payne started both of the first two Tests against the Springboks but will play no part in this weekend's series decider, which is also set to be Eoin Reddan's final appearance for Ireland after he announced his retirement.
Taking Payne's place is Connacht full-back Tiernan O'Halloran, who will make his first start for his country after making his debut as a substitute in last weekend's 32-26 defeat in Johannesberg, while Stuart Olding and Luke Marshall are paired together in the centre.
"It's probably just one day too soon," head coach Joe Schmidt said of Payne's injury. "Jared was looking to train today and wasn't able to.
"At the same time we're looking to give some opportunity to Tiernan and Matt Healy (who could make his debut from the bench) so it was a decision that was made less difficult as a result.
"It was a bit about Jared and a bit about those young lads."
Keith Earls returns to the wing and Ireland coach Joe Schmidt has also recalled Rory Best, Stander and Jordi Murphy to his starting pack. Iain Henderson is back in the second row after starting at blindside flanker last weekend.
South African-born Stander was sent off during the First Test, which Ireland won 26-20 at Newlands, and subsequently banned for one match.
"Mike Ross is coming in fresh, Jordi Murphy and CJ Stander are coming fresh, and hopefully that energy will be a little bit contagious in the group," Schmidt told RTÉ Sport.
"There's a a lot of changes but it's trying to balance players who still have a little bit of fuel in the tank as opposed to players who are either carrying knocks or are just starting to flag at the end of a long season."
Reddan, meanwhile, is set to win his 71st and final cap at the Nelson Mandela Bay Stadium.
The scrum-half has confirmed he will hang up his boots at the end of the season after a glittering career with Munster, Leinster, Wasps, Connacht and Ireland in which he won three Heineken Cups, two Six Nations, a Challenge Cup and two Pro12s.
South Africa have made two changes to their starting XV as they look to follow up last weekend's thrilling win at Ellis Park by claiming a series-clinching victory.
Ruan Combrinck and Warren Whiteley come in for Lwazi Mvovo and the injured Duane Vermeulen. Uncapped back-row Jaco Kriel could make his debut off the bench.
Ireland: Tiernan O'Halloran, Andrew Trimble, Luke Marshall, Stuart Olding, Keith Earls, Paddy Jackson, Conor Murray, Jack McGrath, Rory Best, Mike Ross, Iain Henderson, Devin Toner, CJ Stander, Jordi Murphy, Jamie Heaslip.
Replacements: Sean Cronin, Finlay Bealham, Tadhg Furlong, Ultan Dillane, Rhys Ruddock, Eoin Reddan, Ian Madigan, Matt Healy.
South Africa: W le Roux; R Combrinck, L Mapoe, D de Allende, JP Pietersen; E Jantjes, F du Klerk; T Mtawarira, A Strauss (capt), F Malherbe, E Etzebeth, P-S du Toit; F Louw, S Kolisi, W Whiteley.
Replacements: Bongi Mbonambi, Steven Kitshoff, Julian Redelinghuys, Franco Mostert, Jaco Kriel, Rudy Paige, Morne Steyn, Lwazi Mvovo.
Looking ahead to the final Test, Joe Schmidt said: ""I'm utterly confident that the team will make me and themselves proud," he said.
"They'll make sure that Ireland feel proud of them because that's the way they commit to going about their work and I've no doubt that they'll be no different than it has been in the last two Tests.
"Yes, it's been a long season, people are tired and that's going to maybe detract from people being at their optimum but, at the same time, I don't think too many people will detect that because what they don't have in fresh reserves of energy, they'll make up for it with the full commitment they make to doing the job that they do."
