He was educated at the Catholic St. Aloysius High School and later went into business, eventually running his own coffee import company.

Before becoming mayor, O'Keefe was a prominent member of the Regular Democratic Organization, the political machine that had dominated New Orleans for decades.

He served as the RDO's Tenth Ward boss, the city's Commissioner for Public Finance from 1925 to 1926, and after long-time mayor Martin Behrman died in office O'Keefe was elevated to serve the remainder of Behrman's term.

Under O'Keefe's administration construction was begun on the Municipal Auditorium and plans for the Criminal District Court Building and Orleans Parish Prison were drawn up.

In July 1929, O'Keefe resigned as mayor for health reasons; he was succeeded by T. Semmes Walmsley.