Birney was trained in law and practiced in Danville. He won election to the Kentucky legislature in 1816, and in 1818 he moved to Alabama, where he was elected to the legislature in the following year. There he helped incorporate into the state constitution provisions that empowered the legislature to emancipate slaves and to prohibit selling slaves brought into the state.

In 1837 Birney was elected executive secretary of the American Anti-Slavery Society, which soon afterward split, one faction advocating the inflammatory approach of such abolitionists as William Lloyd Garrison (Garrison, William Lloyd) and the other, which became the Liberty Party, emphasizing electoral activity. The party nominated Birney as its presidential candidate in 1840 and again in 1844. In 1840 he was a vice president of the World Anti-Slavery Convention in England, where he wrote The American Churches, the Bulwarks of American Slavery (1840). Birney's career was ended by an injury that invalided him in 1845.