Lock Henderson comes into the second row alongside Devin Toner, with Donnacha Ryan ruled out due to a knee injury.
Flanker O’Brien has recovered from a calf injury to join CJ Stander and Jamie Heaslip in the back row for the opener at Murrayfield.
Paddy Jackson has been named as fly-half by Joe Schmidt after Jonathan Sexton was ruled out with a calf problem.
Robbie Henshaw and Garry Ringrose will form the centre pairing for an Ireland side who are second-favourites for the tournament behind defending champions England.
Munster hooker Niall Scannell is in line to win his cap from the bench, but his brother Rory misses out.
Ireland team: Rob Kearney, Keith Earls, Garry Ringrose, Robbie Henshaw, Simon Zebo, Paddy Jackson, Conor Murray; Jack McGrath, Rory Best (captain), Tadhg Furlong. Iain Henderson, Devin Toner, CJ Stander, Sean O’Brien, Jamie Heaslip.
Replacements: Niall Scannell, Cian Healy, John Ryan, Ultan Dillane, Josh van der Flier, Kieran Marmion, Ian Keatley, Tommy Bowe.
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