O'Mahony drops to the bench for the clash at King's Park with Caelan Doris taking over as captain.
James Ryan comes in at lock with Tadhg Beirne switching to flanker.
The decision had not gone down well, admitted coach Andy Farrell, but he praised O'Mahony's attitude.
"You don't expect those conversations to be easy and don't get me wrong, he's not accepting and he's not happy obviously but he does the right thing for the team," he said on Thursday.
"That's at the forefront of his mind constantly, and that's proper leadership. He understands that we want to have a look in this direction to see how it goes.
Hooker Dan Sheehan and halfback Craig Casey had already been ruled out after being hurt in last weekend's 27-20 loss to the world champions at Loftus Versfeld in Pretoria.
Sheehan suffered a serious knee injury that could keep him out of action for the rest of the year and is replaced by Ronan Kelleher, who had come in for him in the first test.
Casey suffered concussion after being tackled and is replaced by veteran Conor Murray, who was his replacement in the second half in Pretoria and scored a try.
Bundee Aki is struggling with a shoulder injury and is replaced in midfield by Garry Ringrose.
Six Nations champions Ireland had a long list of injuries at the start of the week but James Lowe (thigh), Jamie Osborne (leg) and Andrew Porter (cut hand) are all fit again.
IRELAND: Jamie Osborne, Calvin Nash, Garry Ringrose, Robbie Henshaw, James Lowe, Jack Crowley, Conor Murray, Caelan Doris (c), Josh van der Flier, Tadhg Beirne, James Ryan, Joe McCarthy, Tadhg Furlong, Ronan Kelleher, Andrew Porter.
Replacements: Rob Herring, Cian Healy, Finlay Bealham, Ryan Baird, Peter O'Mahony, Caolin Blade, Ciaran Frawley, Stuart McCloskey.Â
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