Ryan O’Keefe was educated at St Kevin’s College in Melbourne, where he was the football team captain. He played for the Calder Cannons in the TAC Cup. In 1999, Ezra Bray lived with O’Keefe’s family whilst on an AFL scholarship to attend Essendon Keilor College.

O’Keefe was drafted in the 1999 AFL Draft with the 56th selection.

In 2002, O’Keefe’s younger brother Aaron died in a car accident. His family had lost another son at nine months of age to sudden infant death syndrome when Ryan was 5 years old. He also has a younger sister and brother. His father Brian played football for Fitzroy reserves and his grandfather Lionel Ryan played for Footscray in the 1950s.

He was nominated for the Cleo Bachelor of the Year in 2005 and once dated Mary, Crown Princess of Denmark.

In 2006, he made All-Australian selection, and was once again selected to represent Australia in the International Rules series. He had a highly successful series, scoring more points than any other player. He was awarded the Jim Stynes medal for the best Australian player in the series.

Following the 2008 Grand Final, O’Keefe signalled his intentions to continue his career elsewhere, specifically in Victoria – his place of birth, after knocking back an initial three-year contract offer by the Swans. After a suitable swap was not able to be arranged during the AFL’s “trade week,” however, O’Keefe decided against entering a pre-season draft where three teams outside Victoria had picks before any other Victorian teams. He then signed a 4-year contract with the Sydney Swans.

In January 2008 O’Keefe married Tara Duggan and together they have a son Levi born September 2009 and a second child, Savannah, born in April 2012.

After a very impressive first month of play in 2010, O’Keefe suffered a concussion against the Brisbane Lions at the SCG which somewhat stalled his season. He also sustained a groin injury later in the year which severely hampered his ability to cover the ground with his elite endurance. Accordingly, he was prevented from spending whole games in the midfield and towards the end of the year he spent more and more time in the forward line. O’Keefe did manage to play some impressive football however, particularly against Hawthorn at the SCG when he blanketed Luke Hodge while kicking four goals himself (he was awarded three Brownlow votes for his game). Since the end of the season, O’Keefe has had groin surgery and will be able to participate in pre-season training.

Having recovered from his debilitating groin injury in 2010, O’Keefe returned to very strong and consistent form in 2011. He spent most of his time in the midfield, though did play some meaningful roles up forward late in the year, kicking 4 goals in the Elimination Final against St.Kilda at Etihad Stadium in a BOG performance and then kicking 3 the next week against Hawthorn in the Swans’ Semi Final Loss at the MCG. O’Keefe finished 4th in the Bob Skilton Medal count for season 2011.

O’Keefe won the Norm Smith Medal after his side the Sydney Swans beat Hawthorn by 10 points in the 2012 AFL Grand Final, the first Swans player to do so since the medal’s inception in 1979. O’Keefe finished 3rd in the 2012 Bob Skilton Medal after a superb season. He combined magnificently with the likes of Skilton Medal winner Josh Kennedy, Jarrad McVeigh, Kieren Jack, Lewis Jetta, Dan Hannebery and Craig Bird to become one of the best midfields in the competition. In August 2014, O’Keefe quit the Swans due to limited opportunities and was hoping to be picked up by another club next year. However, he announced his retirement a month later on in September, stating his intention to finish his career as a one-club player for Sydney.

In October 2014, O’Keefe was appointed as a midfield development coach at Adelaide to begin his coaching career. In November 2016, he was appointed as coach of the club’s SANFL team. After two years with Adelaide, O’Keefe replaced Torin Baker in December 2018 as coach of the Western Jets in the TAC Cup.