In 1866, he published a short story in the Atlantic Monthly resting upon both somatic and psychological insights entitled "The Case of George Dedlow". From that point onward, Mitchell divided his attention between scientific and literary pursuits. 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.