O'Rourke boxed in his youth, but his primary talent was rowing. He began managing boxers in the late 1880s, finally getting the black bantamweight George Dixon in his stable in 1889. O'Rourke saw Dixon outmatch Paddy Kelly in Boston, and began managing him to an eventual meeting with Cal McCarthy, the lightweight champion of the world. The bout ended in a draw, so O'Rourke and Dixon took their show on the road, eventually claiming the world championship in 1891, and the featherweight championship in 1892 in New Orleans in a rare (for the time) mixed-race bout, a tribute to O'Rourke's matchmaking abilities.
In addition to Dixon, O'Rourke managed Joe Walcott (note: not Jersey Joe Walcott, who took his name from O'Rourke's boxer), who won the welterweight championship of the world in 1901. Walcott and Dixon are famous for traveling with O'Rourke in a "take on all comers" tour, where O'Rourke had his own, slightly smaller than usual, boxing ring for the bouts. The smaller ring gave his boxers an advantage, as both men were known for their straightforward style.
The number one fighter that he began managing was George Gardner, once the Light Heavyweight Champion of the World in 1903. Gardner won the title from Jack Root and lost the title to Bob Fitzsimmons. It is often thought that the Fitzsimmons match was a publicity stunt, possibly a bribery making Fitzsimmons the first triple title champion in boxing history.