Spence was born in Melrose, Scotland, as the fifth child in a family of eight. In 1839, following sudden financial difficulties, the family emigrated to South Australia, arriving in November 1839 on her 14th birthday at a time when the colony had experienced several years of drought and the contrast to her native Scotland made her "inclined to go and cut my throat". Nevertheless, the family endured seven months "encampment" growing wheat on an eighty acre (32 ha) selection before moving to Adelaide.

Catherine had a talent for writing and an urge to be read, so it was natural that in her teens she became attracted to journalism through family connections, beginning at first with short pieces and poetry published in The South Australian. She also worked as a governess for some of the leading families in Adelaide at the rate of sixpence an hour.

Her first major work was the novel Clara Morison: A Tale of South Australia During the Gold Fever, submitted to and rejected by the same publishers who had initially rejected first novel some years previously, but published by J W Parker and Son in 1854. She received forty pounds for it, but was charged ten pounds for abridging it to fit in the publisher's standard format. Her second novel Tender and True was published in 1856 and to her delight went through a second and third printing, though she never received a penny more than the initial twenty pounds.In 1888, she published A Week In the Future a tour-tract of the utopia she imagined a century in the future might bring, one of the precursors of Edward Bellamy's 1889 Looking Backward.

Although Catherine never married, receiving two proposals during her life, both of which she rejected, she had a keen interest in family life and marriage, as applied to other people, and both her life's work and writing were devoted to raising awareness and improving the lot of women and children. She successively raised three families of orphaned children - the first being those of her sister Mrs Ward.

Around 1850, having become disillusioned with some doctrines of the Church of Scotland she began attending the Adelaide Unitarian Christian Church in Wakefield Street. She preached her first sermons there in 1878, and filled in for the pastor Dr John Crawford Woods during his absences 1884—90.

There are several memorials to Spence, including a bronze statue in Light Square, Adelaide, the Catherine Helen Spence building in the City West campus of the University of South Australia and the Spence wing of the State Library of South Australia

Her image appeared on the commemorative Federation Australian five dollar note issued in 2001.

In 1975 she was honoured on a postage stamp bearing her portrait issued by Australia Post.

Catherine Helen Spence Street in the south-east of the central business district of Adelaide and one of the four schools at Aberfoyle Park Primary school (S.A.) named Spence also honour her.

Novels

• Clara Morison: A Tale of South Australia During the Gold Fever (1854)
• Tender and True: A Colonial Tale (1856)
• Mr. Hogarth's Will (1865)
• The Author's Daughter (1868)
• An Agnostic's Progress from the Known to the Unknown (1884)
• A Week in the Future (1889)
• Handfasted (1984) Penguin Originals ISBN 0140075054

Non fiction

• The laws we live under (1880)
• State children in Australia: A history of boarding out and its developments (1909)
• Catherine Helen Spence: An autobiography (1910) (unfinished, but completed posthumously by Spence's friend Jeanne Young, working from diaries.)