From 1950 to 1953, O'Donoghue worked as a nursing aide in Victor Harbor. The small local hospital did not run a training course. With the help of the matron, Lowitja applied to be a student nurse in Adelaide. The Royal Adelaide Hospital originally rejected her, but shortly afterwards she was offered a position as a student nurse in 1954. She qualified as a nurse and worked at the Royal Adelaide Hospital until 1961.