Absent from last year’s competition through injury, 34-year-old O’Driscoll, scored one try and made another for Simon Zebo to help Ireland march into a 30-3 lead just after the break.
Wales rallied through tries from Alex Cuthbert, Leigh Halfpenny and Craig Mitchell but could not prevent an eighth straight defeat and fifth in a row on home soil – the most on the spin in their history.
After a cagey opening few minutes it was Ireland who began to exert their dominance and following a maul from a ninth-minute lineout, the visitors found space down the right.
Quick hands from O’Driscoll and Rob Kearney found Craig Gilroy out wide, who couldn’t force his way over but saw his pass back inside knocked on by Wales.
From the subsequent scrum, Ireland worked they way to the right and Jonny Sexton fired a pass into O’Driscoll, who showed great dexterity to gather the ball and pick out the overlapping Zebo, who cruised in for his second try in four Ireland appearances.
With the wind in their sails, Ireland refused to step off the gas and with some shrewd kicking, Sexton ensured Wales were pinned back in their own half.
On 19 minutes, Gilroy was held up just short as Ireland scented a second try and while Sexton somehow contrived to miss a close range drop goal from in front of the posts, referee Romain Poite had already awarded the penalty and the Leinster fly-half made no mistake from the tee.
Wales were shell-shocked and soon after, Dan Biggar, making his first Six Nations appearance, saw his clearing kick charged down by the excellent Rory Best, who fielded the spinning ball on the full.
He found Jamie Heaslip supporting to the right and while the Ireland skipper’s pass was behind Zebo, the Munster flyer pulled off an audacious backheel, straight into his grasp.
And just a few phases later prop Cian Healy barrelled his way over to confirm Ireland’s dominance.
Sexton added the extras and when Mike Phillips was pinged for obstruction on 29 minutes, Wales were 20-0 down and reeling but five minutes later Halfpenny finally got them off the mark when Healy did not release.
With just a few minutes remaining of the half, Wales finally found some forward momentum and with George North and Cuthbert enjoying some rare time on the ball, the hosts desperately trying to find a way over.
But Best forced the turnover with Wales just in front of the posts and Sexton rubbed salt into the wounds in first half injury time with another penalty.
Ireland picked up from where they left off after the break and on 44 minutes, when Kearney was held up just short, O’Driscoll was on hand to dive through a gaping hole in the Welsh defence and over the line for his 26th Six Nations try on the day he equalled the record number of Championship starts, joining former Irish centre Mike Gibson on 56.
Sexton notched the conversion but that stirred Wales into life and the Millennium Stadium faithful finally had something to cheer on 48 minutes.
Biggar picked out the onrushing Cuthbert who brushed off Keith Earls to dart over and dot down, with Halfpenny converting, reducing the score to 30-10.
Ireland could not hit the heights they found before the interval and Wales carried the fight to the visitors, who lost Best to the sin bin for coming in at the side.
And after a concerted period of pressure in the Ireland 22, Jonathan Davies found centre partner Jamie Roberts, who in turn found Halfpenny, who touched down in the corner.
He could not convert but the Welsh tide was unrelenting and Ireland breathed a sigh of relief when they forced a turnover, after another penetrative run from Cuthbert on 63 minutes.
With ten minutes to go Toby Faletau was held up just short of the line but Ireland lost Conor Murray to the sin bin for not releasing and Wales continued to knock on the door with replacement tighthead Mitchell forcing his way over on 76 minutes to trim the score to 30-20.
Halfpenny converted but Wales were ultimately beaten by the clock as Ireland ended a three-match losing streak to the Red Dragons.
MORE: The latest football news
MORE: The latest tennis news
BIOGRAPHY: Ethan Hazard
BIOGRAPHY: Daniel Sturridge