Luke Marshall makes his first start for Ireland in two years in Saturday's opening Test against South Africa.
The Ulster centre was the 24th man during the Six Nations and won the last of his six caps in Argentina in 2014.
Jared Payne, one of six Ulster players who will start at Newlands, is at full-back for the first time for Ireland.
Paddy Jackson gets the nod at fly-half in the absence of injured Johnny Sexton while Jordi Murphy, overlooked during the Six Nations, is in the back row.
Jackson ready to step in
The injury-depleted tourists have made four changes from their last international, a 35-25 win over Scotland in Dublin the Six Nations Championship in March, with Jackson set for a rare start.
"I've been waiting for a chance and now I've got it, I'm grateful it has come," he said.
"There will be nerves but a lot of excitement."
After he named the team, coach Joe Schmidt added: "Paddy has bided his time and will slot in really well".
"I think he's got big boots to fill but he has the right-sized shoes."
Sexton was among several significant injury setbacks for the Irish before the three-test tour but Schmidt said he was pleased with his selection.
"I've got a mix of experience and a lot of energy which could be significant after a long season," he said.
"We are hoping to get a platform to build on and to get something out of this series going forward.
"You are never going to be in a situation where everything works out perfectly but I'm hoping to get enough confidence to build through the series."
New role for Payne
With Rob Kearney and Simon Zebo ruled out through injury, coach Joe Schmidt has opted to move Payne - who has won all 14 of his caps at outside centre - to full-back.
He was been ever-present in the number 15 shirt for Ulster this season but up until now Schmidt has resisted the temptation to select him in the backfield.
Payne has forged a solid midfield pairing with Robbie Henshaw in the past two seasons, and the Leinster-bound centre now shifts to the number 13 jersey to play alongside Marshall, with Andrew Trimble and Keith Earls continuing on the wings.
Iain Henderson, who missed the Six Nations through injury, returns alongside Devin Toner in the engine room, while Jack McGrath, captain Rory Best and Mike Ross make up the front row.
Sean Cronin is preferred to Richardt Strauss as replacement hooker and Ultan Dillane provides second row cover.
Ian Madigan and Craig Gilroy are the backline cover for Saturday's first Test (16:00 BST).
Ireland also play the Springboks in Johannesburg on 18 June and Port Elizabeth on 25 June.
Scrumhalf Faf de Klerk will make his debut for South Africa under new Springbok coach Allister Coetzee.
The Lions number nine is the only uncapped player in the starting line-up, the 24-year-old replacing Ulster's Ruan Pienaar, who made himself unavailable for the series.
Ireland: J Payne; A Trimble, R Henshaw, L Marshall, K Earls; P Jackson, C Murray; J McGrath, R Best, M Ross; I Henderson, D Toner; CJ Stander, J Murphy, J Heaslip.
Replacements: S Cronin, F Bealham, T Furlong, U Dillane, R Ruddock, K Marmion, I Madigan, C Gilroy.
South Africa: W le Roux, JP Pieterse, L Mapoe, D de Allende, L Mvovo; P Lambie, F de Klerk; T Mtawarira, A Strauss, F Malherbe; E Etzebeth, L de Jager; F Louw, S Kolisi, D Vermeulen.
Replacements: B Mbonambi, T Nyakane, J Redelinghuys, P du Toit, W Whiteley, R Paige, E Jantjies, J Kriel.