Joe Schmidt's men must defeat Grand Slam-chasing Wales to have any hope of retaining the championship, but they have been hit by a pair of injuries.
Josh van der Flier was withdrawn in the first half of last week's win over France due to a groin injury and so O'Brien, who lost his place to the winger, is back in the team.
Iain Henderson is also unable to make the trip to Cardiff, meaning Beirne plays for the first time in this campaign.
Beirne made his international debut in Australia last year and has four caps to his name ahead of his Six Nations bow.
Rob Kearney is fit to start, however, having withdrawn late on last week as Jordan Larmour started in his place.
Ireland: Rob Kearney, Keith Earls, Garry Ringrose, Bundee Aki, Jacob Stockdale, Jonathan Sexton, Conor Murray; Cian Healy, Rory Best (captain), Tadhg Furlong, Tadhg Beirne, James Ryan, Peter O'Mahony, Sean O'Brien, CJ Stander.
Replacements: Niall Scannell, Dave Kilcoyne, Andrew Porter, Quinn Roux, Jack Conan, Kieran Marmion, Jack Carty, Jordan Larmour.