The inspirational skipper revealed that he suffered a double injury in a crunching tackle by England centre Jamie Noon in last Sunday's 19-13 victory over England at Lansdowne Road - Ireland's third victory from three matches this year.
"That boy really hits hard," said O'Driscoll, who battled on to score the try which gave Ireland victory.
"I was running on adrenaline after that but I was really sore the following morning.
"It was a dead leg and a stinger on the elbow from his hit."
But O'Driscoll insisted his absence at Twickenham is "just a precaution", although he said: "I'm disappointed.
"I really wanted to play in this big game for such a worthwhile cause but I just have to be careful with more big games coming up. I need to do a full week's training next week."
Sir Clive Woodward, coach to the north side, said: "I promised Ireland coach Eddie O'Sullivan that if there was any doubt about Brian I would leave him out. They have some very important matches coming up."
One change to the squad named on Thursday sees Ireland back-row forward Eric Miller brought in from the bench for Frenchman Olivier Brouzet.
Former England captain Lawrence Dallaglio will lead the northern team, in O'Driscoll's absence.
The Wasps back-row forward was one of five England players chosen by Woodward to start the match, with Leicester's Ollie Smith and Ben Cohen, of Northampton, among the backs and Worcester's Pat Sanderson and Sale's Andy Titterrell chosen in the pack.
"I am delighted that Lawrence is involved as captain," said Woodward.
"He is a proven, outstanding player and he is relishing the prospect of stepping up to the mark and taking on the role of captaincy for this unique match.
"I have spoken to Brian and he is bitterly disappointed not to be playing.
"However, he has come over for the game to show his support from the guys."
Woodward's men will meet a strong southern hemisphere outfit, skippered by Australia scrum-half George Gregan and coached by former Wallaby supremo Rod Macqueen.
Gregan will have three international colleagues - Chris Latham, Phil Waugh and Toutai Kefu - alongside him, while New Zealand have four representatives and South Africa have five starters, four coming in the pack.
The south's team manager Morne du Plessis is pleased with the talent he has at his disposal.
"Rod Macqueen and myself are delighted to put out this line-up to represent the southern hemisphere," he said.
"We feel we are thoroughly worthy of representing the southern hemisphere on this great occasion and for such an important cause