Spence's first work, before the age of 30, was the novel Clara Morison: A Tale of South Australia During the Gold Fever. It was initially rejected but her friend John Taylor, found a publisher in J W Parker and Son and it was published in 1854. Spence received forty pounds for it, but was charged ten pounds for abridging it to fit in the publisher's standard format. It was given good reviews, and was the first novel written in Australia by a woman. At the same time Spence became employed as a journalist on The Register, but not initially with her own byline.
Around 1854, having become disillusioned with some doctrines of the Church of Scotland, she began attending meetings of the Adelaide Unitarian Christian Church. She preached her first sermons at the Wakefield Street church in 1878, (though she was not the first woman to preach there, that honour going to Martha Turner of Melbourne, sister of Gyles Turner) and she filled in for the minister J. Crawford Woods during his occasional absences between 1884 and 1889.