He made his Munster debut in 1998 against Neath. During his professional career, O'Driscoll has also played for USA Perpignan in France. Mostly a second-row in his time in Ireland, he often played in the back-row in France. He returned to Munster in 2005 and became an important member of the Munster squad. He won the Munster Player of the Year award for the 2009/10 season. O'Driscoll became the eighth Munster player to win 200 caps for the province on 3 March 2012, during a league game against Newport Gwent Dragons. It was announced on 17 April 2012 that O'Driscoll would be retiring from rugby at the end of the 2011–12 season. His last game for the province was the away league play-off semi-final against Ospreys on 11 May 2012, which Munster lost 45-10. It was announced on 10 April 2014 that O'Driscoll would be joining Munster's coaching staff from 1 July 2014 as a Technical Advisor. O'Driscoll will also be responsible for Munster A.
His international debut came as a replacement against Romania in 2001. O'Driscoll won 23 caps for Ireland, the last of which came against Scotland in the 2011 Rugby World Cup warm-ups. He was a member of Ireland's 2009 Grand Slam winning team. He was selected in Ireland's 2011 World Cup training squad for the warm-up tests in August, but was not selected in the final 30-man squad for the World Cup.