The decisive moment 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 139th Test appearance ahead of his looming retirement, stood with hands on his hips in frustration as Care dashed over.
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. For the second successive game Mike Brown was named man of the match. 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. A breathless first quarter continued to unfold at speed and it was Ireland who poured forward. The 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.
Owen Farrell conceded a penalty for a late tackle on Conor 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 before England suffered a blow when Billy Vunipola fell on his right ankle and had to be replaced by Ben Morgan. England captain Chris Robshaw made a brave call with a minute of the first half left, 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.
Head coach Lancaster claimed the win was the most significant of his two years in charge. He said: "Given the experience of Ireland, the form they were in, and the players they have and some of relative inexperience we have in our team, I'm so proud of the boys," he said. "Delighted for them."
England: Brown, Nowell, Burrell, Twelvetrees, May, Farrell, Care, Marler (M Vunipola 63), Hartley (T Youngs 74), Wilson (Thomas 69), Launchbury, Lawes, Wood
(Attwood 69), Robshaw, B. Vunipola
Ireland: R. Kearney, Trimble (McFadden 65), O'Driscoll (Jackson 79), D'Arcy, D. Kearney, Sexton, Murray (Boss for Murray 79), Healy (McGrath 71), Best (Cronin for Best 73), Ross (Moore 61), Toner, O'Connell, O'Mahony, Henry (Murphy 73), Heaslip
Referee: C Joubert (South Africa)