As a child, Brian played Gaelic football before switching to rugby. For his secondary education, he attended Blackrock College, where he played in the Senior Cup team in 1996 and 1997 after coming up through the ranks from the lower-level teams.

Although O’Driscoll started the first two rounds of the competition in 1996, he was subsequently dropped to the bench for the remainder of the competition, and was an unused replacement in the team’s victorious final appearance, in which Leo Cullen and Bob Casey were the second row. In 1997 they were beaten in the quarter-final by Clongowes, who had Gordon D’Arcy in their side. He was capped three times for Ireland Schools in 1996.

In 1998, O’Driscoll played for the Ireland U-19 side, which won the Under 19 Rugby World Championship. After leaving school, he attended UCD on a scholarship. At UCD, he first made the under-20 side, before being promoted to the top team near the end of his first year. After two years, O’Driscoll graduated from UCD with a diploma in sports management. While at UCD, his coach John McClean moved O’Driscoll from the fly-half position to centre. O’Driscoll made his Ireland under-21 debut in February 1999, and eventually gained four caps.

O’Driscoll made his debut for Leinster in 1999, and under head coach Matt Williams and backs coach Alan Gaffney he became an explosive force in the Leinster backline, forming a highly effective centre partnership with Shane Horgan. In 2001, Leinster won the inaugural Celtic League beating Munster in Lansdowne Road. In 2003, Leinster were heavy favourites for that year’s Heineken Cup but were beaten by Perpignan in the semi-finals.

In 1999, O’Driscoll was selected for the senior squad and was on the bench for a match against Italy, although he did not play. He won his first Test cap at age 20 on 12 June 1999 in a 46–10 loss to Australia in Brisbane as part of the tour of Australia. O’Driscoll played for Ireland before he played for the senior Leinster team.

In 2000, O’Driscoll scored a Hat-trick of tries in a Six Nations Championship victory against France in Paris, propelling Ireland to their first win in Paris since 1972.

O’Driscoll has appeared three times for the invitational Barbarians rugby team: against South Africa on 10 December 2000, against Scotland on 22 May 2004, and against England on 30 May 2004. Against South Africa, O’Driscoll scored his only try as a part of the Barbarians team.

O’Driscoll appeared in all three British and Irish Lions Tests on the team’s 2001 tour of Australia where he announced himself as a world star with an outstanding individual try in the 1st Test victory at the Gabba in Brisbane.

In 2001, 2002 and 2009, O’Driscoll was nominated for the IRB World Player of the Year. In 2001, he lost out to his Irish teammate Keith Wood; in 2002, to Fabien Galthié; and, in 2009, when widely regarded as favourite for the award, to Richie McCaw by a solitary point, with one judge, who would otherwise have given O’Driscoll the award, citing a flawed voting system.

O’Driscoll’s popularity in Ireland was expressed by supporters wearing T-shirts bearing the motto “In BOD We Trust”. In 2002, O’Driscoll was handed the captaincy for the first time in Ireland’s 18–9 win over Australia, the first Irish victory over the Wallabies since 1979. In 2003, following the international retirement of long-time Ireland captain Keith Wood, O’Driscoll was awarded the captaincy on a permanent basis. In that year, O’Driscoll led Ireland to second place in the Six Nations Championship. This was followed by Triple Crowns in 2004 (Ireland’s first crown since 1985), 2006 and 2007. In 2004, O’Driscoll captained Ireland to a 17–12 victory over South Africa, the first Irish win over the Springboks since 1965.

O’Driscoll was named captain of the team for their 2005 tour of New Zealand. Prior to that tour, he had been named captain of the Northern Hemisphere side for the IRB Rugby Aid Match (a 2004 Indian Ocean tsunami fundraiser) held at Twickenham in March 2005, but was forced to withdraw due to a shoulder injury, but appeared pitch-side for the match. O’Driscoll’s playing contribution to the 2005 Lions ended in the opening minutes of the first Test against the All Blacks in Christchurch on 25 June 2005, when he was carried off the field on a stretcher with a shoulder injury just after being spear tackled in tandem by All Blacks skipper Tana Umaga and Keven Mealamu after the ball had been cleared out of a ruck. He extended one arm to protect his head, and his shoulder was dislocated on impact.

He was in a long-term relationship with Irish model and TV3 Xpose presenter Glenda Gilson for a number of years until they split up in 2005. In his autobiography he reveals that he received some playful teasing over the relationship from his teammates.

O’Driscoll was chosen as Player of the Tournament in the 2006, 2007 and 2009 RBS Six Nations Championships.

In 2007, Wasps beat Leinster in the quarter-finals of the Heineken Cup. In 2008, Leinster lost in the group stages. In 2007, Leinster reached the final hurdle of the Magners league only to be denied by the Ospreys and Cardiff. In 2008, Leinster won that title ahead of Munster, marking O’Driscoll’s second honour with the province, his first and only as captain.

In 2007, former England centre and captain Will Carling published his list of the ’50 Greatest Rugby players’ in The Daily Telegraph, and ranked O’Driscoll the tenth greatest player of all time. In summer 2008, he received the Dubliner of the Year Award from The Dubliner magazine. In January 2010, he was voted World Rugby Player of the Decade (2000–09) by the magazine Rugby World.

He has published one book, A Year in the Centre (2005), a memoir of a year as a professional rugby player. A biography, called In BOD We Trust, by Marcus Stead was published in March 2008. A revised and extended version of Stead’s book was published in August 2011, Brian O’Driscoll: The Biography. In February 2011, O’Driscoll and his wife were invited to the wedding of Prince William, Duke of Cambridge, and Catherine Middleton, but only Huberman attended, because of his club team’s (Leinster) preparation for their Heineken Cup semi-final against Toulouse the day after the wedding.

The 2008–09 season marked a shift in focus for O’Driscoll. While retaining the Irish captaincy under new coach Declan Kidney, he handed the honour of Leinster captain to Leo Cullen. O’Driscoll scored two tries in the defeat of English champions London Wasps, however this victory was followed by away defeats for Leinster to both London Wasps and Castres. Leinster advanced to the quarter-finals to face Harlequins at the Twickenham Stoop. When O’Driscoll was absent through injury in April 2009, Leinster relinquished their Magners League crown to Munster at Thomond Park. Against Harlequins, Leinster scored a 6–5 victory, the game infamous for the Bloodgate incident.

In the semi-final against rivals Munster in Croke Park, an 82,206 sell out, O’Driscoll was awarded the man of the match award (which he later dedicated to the entire team) after an intercept try completed a convincing win for Leinster and sent O’Driscoll to his first Heineken Cup final. Leinster captured the Heineken Cup against Leicester Tigers on 23 May 2009. The 19–16 Heineken Cup victory included a drop goal from O’Driscoll who was suffering from a shoulder injury.

In 2009, O’Driscoll was again selected as captain, leading Ireland to win the Triple Crown, Six Nations Championship and their first Grand Slam in 61 years. He scored a try in every match except one, culminating in a 17–15 victory in Cardiff in which O’Driscoll again scored a try and was the RBS man of the match. On 27 March 2009, he was named as player of the 2009 Six Nations Championship, winning the fans’ online poll. In May 2009, he was named the Bord Gáis Energy IRUPA Players’ Player of the Year for the past season.

On 15 November 2009, in a 20–20 draw against Australia at Croke Park, O’Driscoll scored a last minute try. The next day, he was named as one of the seven nominations for the 2009 International Rugby Board player of the year, but controversially missed out to Richie McCaw for this title by a solitary point.

On 21 April 2009, O’Driscoll was selected as part of the 2009 British & Irish Lions tour to South Africa. On 1 June 2009, he was named as captain of the Lions for the game against the Golden Lions taking place on 3 June, in place of the rested Paul O’Connell. He was also named in the outside centre position for the Lions in their first test of the 2009 tour against South Africa, in which he made two assists as the Lions lost 26 – 21. He was forced to withdraw from the tour on 30 June before the third and final test due to a head injury and subsequent concussion he suffered in the second test.

O’Driscoll started for and captained Ireland for every match during the 2010 Six Nations Championship. He picked up his 100th test cap for Ireland against Wales. He scored his 40th test try against New Zealand on 12 June 2010. He started every match for Ireland in the 2010 Autumn Tests. He played for Ireland in the last four World Cups (17 caps, 7 tries). He became Ireland’s most capped player on 26 June 2010 against Australia, winning his 103rd cap.

O’Driscoll married actress Amy Huberman in July 2010 in Lough Rynn Castle. Their first child, a daughter named Sadie, was born just hours before a Six Nations clash with England on 10 February 2013. Their second child, a son named Billy, was born on 20 November 2014. In September 2020, it was announced that they were expecting their third child.

In the 2010–11 season, O’Driscoll won his second Heineken Cup with Leinster. Having suffered a knee injury in a Magners League game one week before the final, O’Driscoll was a major doubt, but he recovered sufficiently and was named in the starting XV. In the final held at the Millennium Stadium, Cardiff on 21 May 2011, Leinster came from behind to defeat Northampton 33–22.

In the 2011 Six Nations Championship, O’Driscoll’s 47th minute try against England, took him past Ian Smith’s 78-year-old record of 24 tries to become the leading Championship try scorer of all time with 25 Tries. The same day, O’Driscoll tied John Smit’s International Captaincy caps record of 75.

On 18 May 2011, O’Driscoll attended a state dinner hosted by President Mary McAleese to mark Queen Elizabeth II’s visit to the Republic of Ireland.

In the 2012 Heineken Cup Final O’Driscoll won his third Heineken cup with Leinster. They beat Ulster 42–14 in an entertaining battle. Seán O’Brien opened the scoring for Leinster to put them ahead 7–3. At half time the score was 14–6, with Cian Healy scoring the second try for Leinster but there was still a lot to play for. A penalty try was then awarded for Leinster but Ulster pulled a try back from second-row Dan Tuohy. Heinke van der Merwe then settled the game with a try for Leinster and Seán Cronin made sure of Leinster’s success.

He returned as captain for the tour of New Zealand in 2012 and he also equalled John Smit’s record as captaining an international side (83 times) but All Black Captain Richie McCaw tied the O’Driscoll/Smit record during the 2013 Rugby Championship against South Africa and McCaw overtook the record when playing in Japan on 2 November 2013. O’Driscoll was fit to play in the 2013 tournament, but before the tournament it was announced that O’Driscoll, who had missed the Autumn internationals earlier that season through injury, would not be reinstated as captain. Declan Kidney named O’Driscoll’s Leinster teammate Jamie Heaslip as captain, in his place. O’Driscoll still started each game of the game of the 2013 Championship for Ireland.

O’Driscoll said in September 2013, that the 2013–14 season would be his last before retiring.

On 30 April 2013, O’Driscoll was named in the squad for his fourth British & Irish Lions tour. O’Driscoll is only the third player in 125 years of the tournament to achieve this. The tour commenced on Saturday 1 June 2013 when the Lions beat the Barbarians at the Hong Kong Stadium. He was selected at outside centre for the first two tests of the tour. He was controversially dropped from the squad for the final test, which the Lions won by 41 points to 16.

O’Driscoll has received Honorary Doctorates from Dublin City University in 2013, Queen’s University Belfast in 2014, and Trinity College Dublin in 2017.

His final appearance for Leinster, and for any team, was in the 2014 Pro12 Grand Final on 31 May in Leinster’s home ground, the RDS in Dublin, in which Leinster defeated the Glasgow Warriors 34–12. He left the field injured early in the first half to be replaced by Ian Madigan. His final act as a rugby player was assisting club captain Leo Cullen – who also finished his career on this day – in lifting the Pro12 trophy

On 8 March 2014, in his last home international for Ireland, O’Driscoll led the team out against Italy in the 2014 Six Nations Championship and contributed to three tries in the game as Ireland won 46–7, for which he was awarded Man of the Match. At this point O’Driscoll achieved a world record for the highest number of international caps, with 140, overtaking George Gregan’s record with Australia.

In his last international match, the finale of the 2014 Six Nations Championship on 15 March 2014, O’Driscoll and the Irish team beat France in Paris for only the second time in 42 years, crowning Ireland the 2014 Six Nations Championship champions. In the post-match interview, an emotional O’Driscoll remarked he could not have wished to finish his career in a better way.

Pitch-side at the Hong Kong Sevens in March 2014, former Ireland and British and Irish Lions captain Brian O’Driscoll and former Australia captain George Gregan demonstrated their skills to Bloomberg TV Anchor John Dawson.

In June 2014, it was announced that he would be joining Newstalk as a rugby pundit and co-presenter on Off The Ball. He also works for BT Sport as an analyst. O’Driscoll was part of ITV Sport’s team of studio pundits for the 2015 Rugby World Cup in England, and has continued to work for ITV during their coverage of the Six Nations Championship from 2016 onwards.

In October 2014, O’Driscoll’s new book The Test: My Autobiography was published. It was originally to be written by award-winning sports journalist and ghostwriter Paul Kimmage, but the relationship between O’Driscoll and Kimmage broke down after three years of work together. The book won Sports Book of the Year at the 2014 Irish Book Awards.