Silas Weir Mitchell was born in Philadelphia, Pennsylvania, on February 15, 1829, to John Kearsley Mitchell (1798-1858) and Sarah Henry Mitchell (1800-1872). His father was a physician with a successful medical practice and was a professor at Jefferson Medical College. As a child, Mitchell constantly studied religion and was required to read a portion of the Bible daily, as well as attend church twice on Sundays, where he would often read novels. At the age of fifteen, when he first joined the University of Pennsylvania, he preferred to play billiards and write poetry rather than study subjects like mathematics. However, in his second year at the university, he ranked first in his class. After his third year, Mitchell was forced to withdraw from school, due to his father's critical illness, and he enrolled in Jefferson Medical College in 1848. He finished the two-year course at age twenty-one with an M.D. Immediately after graduation, he left for Paris with his sister, Elizabeth, and studied medicine. He was influenced strongly by Claude Bernard and Charles Philippe Robin. After a year abroad, he was forced to return once again to help his father with his medical practice, working with his father during the day and in the laboratory during the night. His father retired from work in 1855, and Mitchell was then responsible for supporting both his parents and his siblings. When his father died in 1858, he took over the practice and continued the practice until he died in 1914. In Philadelphia, in 1858, he married Mary Middleton Elwyn, who gave birth to their two sons, John K. Mitchell and Langdon Elwyn Mitchell. His wife died in 1862. In 1875, he married his second wife, Mary Cadwalader, a daughter of one of the most prestigious families of Philadelphia, who bore his daughter, Maria Gouverneur, in 1876. This marriage elevated him into one of the city's highest social circles and gave him the freedom to take on almost any scientific endeavor.

The American Civil War served as a starting point in Mitchell's life long study of nervous diseases when he was in charge of nervous injuries and maladies at Turner's Lane Hospital in Philadelphia. Here, he pursued his interest in nerve wounds and diseases, and by the end of the war, Mitchell was a neurology specialist and wrote several works, including Reflex Paralysis and Gunshot Wounds and Other Injuries of Nerves, both published in 1864. In the latter, the first reference is made to causalgia, which was more thoroughly described in the 1872 book, Injuries of Nerves and Their Consequences. After receiving distinction on his accomplishments at Turner's Lane Hospital, Mitchell set up his own private practice, and in the early 1870s, he was appointed to the Philadelphia Orthopaedic Hospital and Infirmary for Nervous Diseases. It was during his time here that he gave the first description of erythromelalgia, an intensely painful nervous condition in which the patient manifests elevated skin temperatures and burning sensations. It also became known as Mitchell's Disease, named after him since he was the first descriptor of the condition. Mitchell's greatest fame in the medical world came from a method he developed in the early 1870s for the treatment of a variety of nervous conditions. It was a method that emphasized isolation, bed rest, dieting, and massage. Particularly targeting women, the "Weir Mitchell Rest Cure" became recognized throughout the United States and Europe and even drew the attention of Sigmund Freud and French neuropathologist Jean Martin Charcot. Mitchell's Wear and Tear / Hints for the Overworked (1871) and Fat and Blood: An Essay on the Treatment of Certain Forms of Neurasthenia and Hysteria (1877) were best-selling publications of his theories, were published in many editions, and were translated into four different languages.

From the early 1860s until his death, Mitchell produced poetry as well as fictional work, but he published these under the pseudonym of Edward Kearsley to keep his literary and his medical careers separate. In 1863, he wrote a short story that combined physiological and psychological problems, The Case of George Deadlow, and had it published in the Atlantic Monthly Magazine anonymously. This story follows a doctor who creates bizarre professions, including a homeopathic physician, an expert in vegetable remedies and "electromagnetic" treatment. This story was considered one of Mitchell's best, because it carried a sense of humor and a bit of satire. Mitchell eventually did admit his secret penname in 1880 after the publication of his first fiction book, Hepzibah Guiness. Afterwards, his focus moved slowly away from his medical work and more towards creative writing. He published another novel, In War Time, in 1884, which provided a lucid description of the Civil War and its psychological effects on those impacted by it. Mitchell's most popular book was Hugh Wynne, Free Quaker (1898), which was a historical fictional novel taking place in Philadelphia during the American Revolution. A New York Critic contributor declared: "It will be long before we see a better novel of the last century in America." Many of Mitchell's works have some traces of personal experiences in them, and this particular novel demonstrates his practice in the medical field, through the real-life descriptive details. Though the story was criticized for lacking a strong plot, the characterization in the book has great depth, and Mitchell received significant credit for it. Mitchell wrote poetry, in addition to his novels, including his most popular "Ode on a Lycian Tomb," which was written about his daughter who died in 1898 from diphtheria. Unlike his other poetry, this poem is extremely personal, and it speaks honestly to the reader about loss and grievance.

By the end of his life, Mitchell considered himself a physician who wrote novels, as opposed to a novelist with an M.D. He received many honors between his two careers. For his studies of medicine, he was made a trustee of the University of Pennsylvania in 1875, was elected as the first president of the American Congress of American Physicians and Surgeons in 1889, and made a trustee of Carnegie Institution of Washington in 1902. For his fictional writing, he received honorary LL.D.s from Harvard, Princeton, and the Universities of Edinburgh and Toronto. Mitchell contracted influenza in 1913, and he died in his Philadelphia home on January 4, 1914.