England don't Care about O'Driscoll
The decisive moment of a compelling encounter arrived with Danny Care's 57th minute try, enabling Stuart Lancaster's men to turn a 10-6 deficit into a 13-10 lead that they never relinquished.
O'Driscoll, making a record-equalling 139th Test appearance ahead of his looming retirement at the end of the season, stood with hands on his hips in frustration as Care dashed over.
The 35-year-old's 13th and final appearance against England ended in bitter disappointment as Ireland's Triple Crown and Grand Slam ambitions evaporated with their first defeat of the Championship.
When Rob Kearney capitalised on slack defending to touch down under the posts, the Irish had established a commanding position underpinned by a 10-3 lead.
But the Red Rose rallied with a display of trademark character to register their fourth successive victory in the fixture.
Remarkably, the score had been limited to just 3-0 in England's favour at half-time as defences reigned, the rivals taking it in turns to trade blows in an absorbing contest.
Ireland's starting XV contained 422 more caps at 724, but it was panic-free England who looked the grizzled band of proven veterans in a nerve-shredding final quarter.
For the second successive game the magnificent Mike Brown was named man of the match with his run to set up Care's try the high point of another outstanding afternoon.
The Harlequins full-back was influential as England made a bulldozing start, producing a diving catch off O'Driscoll's chip and then speeding free from the breakdown.
Seventeen phases passed as the Irish defence came under pressure, but when England went wide in search of the try they blundered, Owen Farrell delaying his pass to Billy Twelvetrees which reduced the space available.
The whitewash still beckoned for Jonny May only for the Gloucester wing to drop the ball over the line following a double tackle from Andrew Trimble and Conor Murray.
A breathless first quarter continued to unfold at breakneck speed and now it was Ireland who poured forward, going inches close twice through Trimble after quick hands in the backs.
An impressive start from the Irish gave way to a renewed attack from England, although their efforts lacked the imagination and skill displayed by their opponents.
Farrell conceded a penalty for a late tackle on Murray as the move died out, but once that had been defended the Saracens fly-half landed the first points of the match in the 23rd minute.
The frantic pace finally slowed in the second quarter, but Ireland were still looking to put as much speed on the ball as possible when they attacked.
Seizing the opportunity to drain the stamina of tighthead David Wilson, who has been limited to just 47 minutes of rugby in two months because of a calf injury, they opted for a series of scrums.
Having attempted to soften up England at the set piece, they probed out wide on the left on two occasions, but the defence to keep Dave Kearney wrapped up was superb.
Farrell struck the left post with a second penalty attempt before England suffered a damaging blow when Billy Vunipola fell awkwardly on his right ankle and had to be replaced by Ben Morgan.
Captain Chris Robshaw made a brave call with a minute of the first half remaining, opting for touch instead of taking a long-range shot at goal and the gamble failed when Luther Burrell knocked on.
Just 82 seconds after the interval Ireland raced ahead when Jamie Heaslip sent Rob Kearney darting through a hole at the breakdown on the 22 and the Leinster full-back easily evaded Brown.
The gap in England's defence was compounded by the fact it was tight five forwards Wilson and Joe Launchbury who attempted to close the space and there was only one winner when Heaslip teed up Rob Kearney.
Sexton converted and added a penalty, but the deficit was slashed to four points by Farrell following a great passage of play from the Red Rose that almost saw Burrell squeeze over.
The pivotal moment arrived 16 minutes into the second half with an outstanding try launched by Robshaw's break through the midfield.
Robshaw fed Harlequins team-mate Brown and just as the full-back was hauled down, Care grabbed his pass and raced in under the posts with Farrell converting.
England needed to summon on their depths of character as they repelled a driving maul that showed Ireland were far from finished as an attacking force.
Dave Kearney tripped as Ireland staged one final attack and once more the home defence held firm, snuffing out the final throws of Irish resistance.