Australia head coach John Connolly has rejigged his backline again with Stirling Mortlock forging a potentially destructive centre partnership with Lote Tuqiri.
Tour skipper Mortlock made a try-scoring return from knee surgery in last weekend's 25-18 victory over Italy and although a proven international, has little Test experience in the number 12 jersey.
Rugby league convert Tuqiri has featured mainly on the wing but was given a run-out at centre in the 29-29 draw with Wales at the start of their European tour.
It is an untried combination that will face the most settled - and arguably most lethal - midfield in Test rugby with O'Driscoll lining up alongside Leinster team-mate Gordon D'Arcy.
D'Arcy was man of the match in Saturday's 32-15 demolition of South Africa and O'Driscoll was not far behind as Ireland's gifted backline ran riot in Dublin.
And, while O'Driscoll is braced for a ferocious Wallabies assault, he knows they will be equally aware of the damage Ireland's midfield is capable of inflicting.
"Australia are trying different combinations, a little like ourselves. This will be their third different centre pairing in three games. They want to see who gels with who," he said.
"You know what you're getting with Mortlock and Tuqiri. They're both very strong, physical players.
"Stirling has a good slight of hand and there have been times when he's been the best centre in the world. He would cause anyone headaches.
"He's one of the best passers in the game and that's part of the thinking of playing him at 12. Guys like him can play anywhere in the backline.
"Apart from gas he'd have no problem playing on the wing, but at the same time the guy is no slouch.
"Tuqiri is direct but at the same time has great footwork. He's physical in the tackle. A lot of the time he beats his opposite number one on one.
"That's what he thrives on and you have to get double teams on him. Our hands will be full against the two of them, but they'll be thinking the same thing about D'Arcy and myself."