He is considered the father of medical neurology, and he discovered causalgia (complex regional pain syndrome) and erythromelalgia, and pioneered the rest cure.

In this field Mitchell pioneered the rest cure for diseases now termed "psychiatric", particularly neurasthenia and hysteria, subsequently taken up by the medical world.

In 1866, he published a short story in the Atlantic Monthly resting upon both somatic and psychological insights entitled "The Case of George Dedlow".

In the former field, he produced monographs on rattlesnake venom, intellectual hygiene, injuries to the nerves, neurasthenia, nervous diseases of women, the effects of gunshot wounds upon the nervous system, and relations between nurse, physician, and patient; in the latter, he wrote juvenile stories, several volumes of respectable verse (The Hill of Stones and Other Poems was published in 1883 by Houghton, Mifflin and Co.), and prose fiction of varying merit, which earned him a leading place among American authors at the close of the 19th century.

His historical novels in particular, notably Hugh Wynne (1897), The Adventures of François (1898), The Youth of Washington (1904), and The Red City (1909), are among the best of their genre.

[1] He would mentor Hideyo Noguchi, helping him get his start in Philadelphia, and co-author papers together on snake venom and toxicity for the University of Pennsylvania's medical journal.

[citation needed] He was Charlotte Perkins Gilman's doctor and his use of a rest cure on her provided the idea for "The Yellow Wallpaper", a short story in which the narrator is driven insane by this treatment.

She was a daughter of Thomas McCall Cadwalader and Maria Charlotte Gouverneur (niece of Elizabeth Kortright, who had married U.S. President James Monroe).

[25] The Philadelphia Chippendale chairs seen in several Eakins paintings – such as William Rush Carving his Allegorical Figure of Schuylkill River (1877) and the bas-relief Knitting (1883) – were borrowed from Mitchell.

Following Eakins's 1886 forced resignation from the Pennsylvania Academy of the Fine Arts, Mitchell may have recommended the artist's trip to the Badlands of South Dakota.

[26] Mitchell commissioned Saint-Gaudens to create a monument to his deceased daughter Maria: The Angel of Purity, a white marble version of the sculptor's Amor Caritas.

The story tells how a very young girl in rags and threadbare shawl came to his door in bad weather and begged him to come take care of her sick mother.

A 2011 study determined that the ghost story was likely originally told by Mitchell himself as entertainment at a medical meeting, then took on a life of its own.

[27] Charlotte Perkins Gilman would claim her short story "The Yellow Wallpaper" was directed at Weir Mitchell that he might reconsider the rest cure or change his treatments.