O'Driscoll was carried off inside the first two minutes of a ferocious, relentless Test match and the Lions suffered a further blow soon after when Richard Hill limped off after 18 minutes.
The England flanker was later seen hobbling around on crutches after an extensive examination of his knee. His tour might also be over.
The All Blacks took control virtually from the kick-off at the Jade Stadium, dominating territory, enjoying large swathes of possession and forcing mistakes from the Lions which they translated into tries for Ali Williams and Sitiveni Sivivatu.
Fly-half Dan Carter, enjoying clean possession on the front foot, won the battle of the stand-offs and he slotted 11 points with the boot.
Stephen Jones and Jonny Wilkinson had their attacking influence nullified. Wilkinson put in a sterling defensive display at inside centre but was able to contribute only a solitary penalty to the Lions' cause.
The Lions suffered the worst possible start when O'Driscoll was carried off the field inside two minutes.
Will Greenwood, after injury wrecked his previous two Lions tours, came off the bench to win his first cap and slotted into outside centre alongside Wilkinson.
The All Blacks dealt well with a brief burst of Lions pressure and then exploded out of their own territory with a trademark counter-attack and spent most of the next 75 minutes camped inside the Lions' half.
Wilkinson saved the Lions with an astonishing tackle on Howlett when the All Blacks had worked a five-on-one overlap.
Paul O'Connell was then sin-binned for deliberate offside as he made a desperate attempt to close down another clear try-scoring opportunity.
Carter landed the penalty but the Lions, through desperate defence, survived unscathed during their time with a man down. On the scoreboard at least.
Hill limped out of the action and was replaced by Ryan Jones, who made an immediate impact and was a real plus on a difficult night for the Lions.
Chris Jack was fortunate to escape a yellow card for tipping in the line-out but the Lions continued to shoot themselves in the foot.
A rushed cross-kick from a penalty allowed the All Blacks to counter again. Jones tackled Leon MacDonald into touch but a lapse in communication at the line-out allowed Williams to pick off the throw and drive 10 metres for the opening try.
Tana Umaga then chipped through for Sivivatu, who was bearing down on the out-paced Gareth Thomas but he was denied a score by an awkward bounce.
Wilkinson missed a penalty for the Lions just before the interval and they needed to start the second period on top, slow the pace of the game down and reverse the pressure.
However, the opposite happened. First Carter landed another penalty and then Dwayne Peel knocked forward in taking a quick tap penalty. The All Blacks punished him.
Umaga hit the line on a wonderful angle and swung a long pass out to Sivivatu for a breathtaking try.
Wilkinson pulled back a penalty to put the Lions on the scoresheet but the All Blacks were already out of sight.