He studied at the University of Pennsylvania in that city, and received the degree of M.D. at Jefferson Medical College in 1850. During the Civil War he had charge of nervous injuries and maladies at Turners Lane Hospital, Philadelphia, and at the close of the war became a specialist in neurology. In this field Weir Mitchell's name became prominently associated with his introduction of the rest cure, subsequently taken up by the medical world, for nervous diseases, particularly hysteria; the treatment consisting primarily in isolation, confinement to bed, dieting and massage. His medical texts include Injuries of Nerves and Their Consequences (1872) and Fat and Blood (1877). Mitchell's disease (erythromelalgia) is named after him.
In 1863 he wrote a clever short story, combining physiological and psychological problems, entitled The Case of George Dedlow, in the Atlantic Monthly Magazine. Thenceforward, Dr Weir Mitchell, as a writer, divided his attention between professional and literary pursuits. In the former field, he produced monographs on rattlesnake poison, on intellectual hygiene, on injuries to the nerves, on neurasthenia, on nervous diseases of women, on the effects of gunshot wounds upon the nervous system, and on the relations between nurse, physician, and patient; while in the latter, he wrote juvenile stories, several volumes of respectable verse, and prose fiction of varying merit, which, however, gave him a leading place among the American authors of the close of the 19th century. His historical novels, Hugh Wynne, Free Quaker (1897), The Adventures of François (1898) and The Red City (1909), take high rank in this branch of fiction.