The 46 times-capped centre has recovered from a hamstring injury that forced him to miss last weekend's defeat in France.
The British Lion will make his first Test match appearance since the World Cup, as one of two changes coach Eddie O'Sullivan has made two changes following that 35-17 reversal.
O'Sullivan has dropped Bath centre Kevin Maggs and Leinster lock Malcolm O'Kelly, who boast 119 caps between them.
Maggs makes way for O'Driscoll, who will form an all-Leinster midfield combination alongside Gordon D'Arcy.
Munster lock Donncha O'Callaghan replaces O'Kelly.
It will be 24-year-old O'Callaghan's first Test start after winning all eight of his previous caps off the bench. He teams up with Munster second-row colleague Paul O'Connell.
Maggs and O'Kelly drop down to replacement duty, and there is no place in the 22 for Munster wing Anthony Horgan, who went on as a second-half substitute in Paris.
Ireland are bidding for a fifth successive victory over Wales.
Ireland team to play Wales in the RBS 6 Nations Championship at Lansdowne Road, Dublin: G Dempsey (Leinster); S Horgan (Leinster), G D'Arcy (Leinster), B O'Driscoll (Leinster, capt), T Howe (Ulster); R O'Gara (Munster), P Stringer (Munster); R Corrigan (Leinster), S Byrne (Leinster), J Hayes (Munster), D O'Callaghan (Munster), P O'Connell (Munster), S Easterby (Llanelli Scarlets), K Gleeson (Leinster), A Foley (Munster).
Replacements: F Sheahan (Munster), S Best (Ulster), M O'Kelly (Leinster), V Costello (Leinster), G Easterby (Rotherham), D Humphreys (Ulster), K Maggs (Bath).