The experienced and influential quartet missed the entire autumn schedule through injury but return at outside centre, full-back, openside and hooker respectively.
For the first time since succeeding Keith Wood as captain in 2004, O'Driscoll is relieved of the leadership duties following coach Declan Kidney's decision to appoint number eight Jamie Heaslip skipper.
The 34-year-old resumes his centre partnership alongside Leinster team-mate Gordon D'Arcy for a record 48th time with Jonathan Sexton and Conor Murray selected at half-back.
"It was a tight call because there's so much competition. Fergus McFadden and Keith Earls have been playing well, so it's testament to the way Craig and Simon have been playing that they're selected," coach Declan Kidney said.
In total there are four changes in personnel to the side that thumped Argentina 46-24 in the climax to a mixed November, among them Chris Henry's demotion to the bench.
O'Brien was assured of a spot in the back row once he had returned to fitness, but Henry is unfortunate to have made way with Peter O'Mahony preferred at blindside.
"We felt that in terms of a mix in the back row this was the best combination, but there was certainly plenty to talk about following Chris' performances in the autumn," Kidney said.
Ireland, the bookmakers' third favourites to win the Six Nations, have lost their last three matches to Wales, including a 23-21 loss on the opening day of the championship last year.
But while the injury-hit Welsh enter the tournament as champions, they have endured seven successive defeats including a whitewash during a troubled autumn.
R Kearney (Leinster); C Gilroy (Ulster), B O'Driscoll (Leinster), G D'Arcy (Leinster), S Zebo (Munster); J Sexton (Leinster), C Murray (Munster); C Healy (Leinster), R Best (Ulster), M Ross (Leinster), M McCarthy (Connacht), D Ryan (Munster), P O'Mahony (Munster), S O'Brien (Leinster), J Heaslip (Leinster, capt).
Replacements: S Cronin (Leinster), D Kilcoyne (Munster), D Fitzpatrick (Ulster), D O'Callaghan (Munster), C Henry (Ulster), E Reddan (Leinster), R O'Gara (Munster), K Earls (Munster).
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