The Ireland and 2005 Lions skipper is looking forward to the match, in which he will be coached by Ireland boss Eddie O'Sullivan.
O'Driscoll said: "Having previously played for the Barbarians against the Springboks in Cardiff seven years ago and also enjoyed their tour to Scotland and England in 2004, it is a great honour for me to be invited to captain the club in what promises to be another great game against South Africa.
"I have very happy memories of playing for the Baa-Baas against England at Twickenham three years ago and look forward to returning there in December.
"I am looking forward tremendously to preparing for the match with Eddie O'Sullivan as coach and the prospect of many world-class players from several countries as team-mates."
The Barbarians are lining up the cream of world rugby to play in the match.
Those invited include Jerry Collins and Sitiveni Sivivatu from New Zealand, Chris Latham, Matt Giteau and Rocky Elsom from Australia, and Juan Martin Hernandez and Mario Ledesmo from Argentina.
Stars from nearer home include England's Jason Robinson and Andrew Sheridan, French powerhouse Sebastien Chabal and O'Driscoll's fellow Irishman, Paul O'Connell, while Martyn Williams and Tom Shanklin from Wales have also been invited.