O'Driscoll has been ruled out of the entire championship after undergoing shoulder surgery, leaving a void in the position he has filled with such distinction since 1999.
The task of filling some of the biggest boots in world rugby has fallen to Earls, the Munster and Lions back who has scored 11 tries in 26 Test appearances.
Earls has played at outside centre for his province in recent weeks and head coach Declan Kidney felt he was the leading candidate to replace O'Driscoll.
"Keith trained really well last week and it was on that basis that we made the decision," Kidney said.
"He's looking forward to it and obviously has played very well there for Munster.
"All players can adapt. He's played a lot in the position and is comfortable there. Keith has been playing very strongly in the Heineken Cup."
Andrew Trimble of Ulster has been selected on the left wing with Jonathan Sexton and Conor Murray the preferred half-backs.
Sexton has edged out the more experienced Ronan O'Gara, who must settle for a spot among the replacements.
In total there are only three changes, one positional, to the side defeated 22-10 by Wales in last autumn's World Cup quarter-final.
The pack is identical to the eight that suffered heartache in Wellington with Donncha O'Callaghan holding off the challenge of Donnacha Ryan in the second row.
The only Test debutant in the 22 is Munster back row Peter O'Mahony, who features on the bench.
Wales, who are waiting for injury updates on key players Rhys Priestland, Dan Lydiate and Jamie Roberts, name their team for the showdown in Dublin on Friday.
Ireland Team: R Kearney (Leinster); T Bowe (Ospreys), K Earls (Munster), G D'Arcy (Leinster), A Trimble (Ulster); J Sexton (Leinster), C Murray (Munster); C Healy (Leinster), R Best (Ulster), M Ross (Leinster), D O'Callaghan (Munster), P O'Connell (Munster, capt), S Ferris (Ulster), S O'Brien (Leinster), J Heaslip (Leinster).
Replacements: S Cronin (Leinster), T Court (Ulster), D Ryan (Munster), P O'Mahony (Munster), E Reddan (Leinster), R O'Gara (Munster), F McFadden (Leinster).
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