The Ireland skipper, who led the Lions during the tour of South Africa, damaged ligaments during the 17-17 draw and is expected to be out of action for up to six weeks.
If O'Connell is on the sidelines for six weeks he will also miss Munster's crunch Heineken Cup quarter-final with Ulster.
"Paul O'Connell underwent a scan on his left knee after twisting it during the game," read an IRFU statement.
"The scan has shown that he has picked up an injury to his medial collateral ligament.
"The injury will also rule him out of the next two games with an expected three-six week recovery period."
Ireland will also be without scrum-half Conor Murray for the final two matches against Scotland and England, also due to a knee injury.
"Conor Murray was replaced in the 59th minute after falling awkwardly on his right knee," added the IRFU.
"A scan has revealed bone bruising in the joint and while there has been no significant damage done to his ligaments, the injury does rule him out of contention for the remaining two games of the championship with a expected three-four week recovery period."
Munster scrum-half Tomas O'Leary and Connacht forward Mike McCarthy have been added to the squad which meets up again on Monday evening.