In 1872 Spence helped Caroline Emily Clark to found the Boarding-Out Society, to board orphaned, destitute and reformed delinquent children in the homes of families, and visit them to check on their behaviour and treatment. She was an official of the society in 1872-86 and worked strenuously as a visitor. When the State Children's Council was established in 1886 she became a member, and was later a member of the Destitute Board.
Most of her work for education was done with her pen. Spence supported the foundation of kindergartens and a government secondary school for girls. In 1877 she was appointed to the School Board for East Torrens, an ineffectual and short-lived body. Her book, The Laws We Live Under (1880), was the first social studies textbook used in Australian schools, and anticipated similar courses in the other colonies by twenty years.
R. Barr Smith gave financial backing for her campaign for proportional representation; it was supported by the nascent Labor Party and several small populist and socialist groups, and was launched with widespread public meetings in 1892-93
Spence joined the fight for female suffrage in 1891 and became a vice-president of the Women's Suffrage League of South Australia. After South Australian women were enfranchised in 1894, she supported campaigns in New South Wales and Victoria and spoke at meetings of the Woman's League, a body formed in Adelaide for the political education of women. She urged the establishment of a local organization affiliated with the International Council of Women. This work also won her acclaim; she had become a symbol of what Australian women could attempt. When she died on 3 April 1910 she was mourned as 'The Grand Old Woman of Australia'.