O'Keefe was originally drafted from Calder Cannons in 1999 after a stellar season that earned him a spot in the TAC Cups Team Of The Year. Sydney selected O'Keefe with pick 56 in the same year, slowly but surely he developed into an elite midfielder. In 2005 O'Keefe became a premiership player for the first time when the Swans defeated the West Coast Eagles in a Grand Final thriller. That win broke a 72-year drought for the Swans as they hadn't won a Grand Final since 1933. The Swans faced off against the Eagles again in 2006. O'Keefe was awarded All-Australian that year but the Swans would fall short to the Eagles this time. Seven years later O'Keefe and Sydney returned to claim another premiership victory in 2012. This time, however, O'Keefe was awarded the Norm Smith medal after a decisive performance against Hawthorn. Aside from football O'Keefe also participated in the International Rules test series from 2005-2006. He claimed the Jim Stynes award in his last test series.
In 2014 O'Keefe hung up the boots to pursue a coaching career at Adelaide. For two years O'Keefe was in charge of midfield development for the Crows until he was appointed coach of Adelaide's SANFL (South Australian National Football League) team in November 2016. O'Keefe would coach Adelaide for two seasons but sought new opportunities at the end of 2018. Now in 2019 O'Keefe has replaced Torin Baker as the new head coach of the Western Jets. O'Keefe's 15 years of experience as an AFL player will bring a new culture to the Jets.