Out-half Paddy Jackson and centre Luke Marshall will make their senior debuts for the international side, while Tom Court will win his 30th cap after being selected at loose-head.
Uncapped Jackson has been chosen to replace Jonathan Sexton, who is nursing a hamstring injury, ahead of Ronan O'Gara at fly-half.
The decision is one of the biggest calls of Declan Kidney's five-year reign as head coach.
Marshall will start at inside centre after Gordon D'Arcy was struck down by a foot injury.
The decision to play Jackson is the big talking point given O'Gara's status as Ireland's most capped player with 127 appearances.
The Munster veteran, who turns 36 next month, was expected to be Kidney's automatic choice to replace Sexton given he has served as back-up at fly-half since the 2011 World Cup.
But after a somewhat poor season so far, Kidney is keeping him on the bench this weekend.
Rory Best and Craig Gilroy have also been named to start at hooker and wing respectively, while Declan Fitzpatrick and Iain Henderson have been selected on the bench.
The Ireland team to play Scotland on Sunday in Edinburgh in the RBS 6 Nations, kick off at 2pm.
Rob Kearney ;Craig Gilroy; Brian O'Driscoll; Luke Marshall; Keith Earls; Paddy Jackson; Conor Murray; Tom Court; Rory Best; Mike Ross; Donncha O'Callaghan; Donnacha Ryan; Peter O'Mahony; Sean O'Brien; Jamie Heaslip (Captain).
Sean Cronin; David Kilcoyne; Declan Fitzpatrick; Devin Toner; Iain Henderson; Eoin Reddan; Ronan O'Gara; Luke Fitzgerald.