Joseph Wortis was born in Brooklyn, New York on October 2, 1906, one of five children of a Russian watchmaker and a French Alsatian mother. He attended New York University, where he majored in English literature before switching to a pre-medical course and graduated in 1927. Soon after graduation, Wortis travelled to Europe. Instead of returning to the United States to attend Yale University Medical School in the fall, he spent the next five years studying medicine at the University of Vienna, Medical Faculty (1927-1932) and in Munich and Paris. Upon returning to the United States, Wortis became a resident in Psychiatry at Bellevue Hospital, where he remained for less than a year. Havelock Ellis, the famous writer and sexologist whom he had met while on summer vacation in England in 1927, wrote asking if Wortis would accept a generous fellowship to return to Europe to study problems in the area of homosexuality. Wortis accepted. Mrs. A. Kingsley Porter funded the fellowship. Broad in its mandate, the fellowship allowed Wortis to first develop his skills and training in psychiatry with the expectation that he would later turn his attention to sex research.

Ellis and Adolph Meyer, then Chief of Psychiatry at Johns Hopkins University, became joint sponsors of the fellowship, which Wortis received from 1933 to 1940. The fellowship took Wortis through his studies in England and Vienna and through his residencies at New York University Medical College (1934-1938) and his teaching assistantship in Psychiatry at Johns Hopkins Medical School (1938-1939). In England, Wortis was at Maudsley and Queens Square Hospitals, London, and in Vienna, he was at Neurologic Institute under Otto Marburg.

In 1934, Wortis married Helen Zunser, with whom he had been intermittently involved since his New York University days and who was the daughter of a prominent Jewish literary family. That same year, Wortis began his fellowship by returning to Vienna to undergo didactic psychoanalysis under Dr. Sigmund Freud. Freud analyzed Wortis over a period of four months (October 1933 to January 1934), which Wortis later described in Fragments of an Analysis with Freud. During the same year in Vienna, Wortis met Dr. Manfred Sakel and observed his new insulin shock treatment for schizophrenia. Wortis introduced the insulin treatment when he returned to America in 1935. Later her translated Dr. Sakel's German monograph on the treatment and helped bring Dr. Sakel to America.

For several years thereafter, Wortis served as Research Fellow and later managed the treatment ward and research laboratory on brain metabolism at Bellevue Psychiatric Hospital, where he remained Clinical Professor of Psychiatry until 1953. From 1941 to 1943, Wortis worked at Columbia University as a Research Associate in Physiology and as a Physiological Investigator at the Aviation Research Laboratory. During World War II, he served as Chief Psychiatrist (Lieutenant Commander) at the New York Port Office of the War Shipping Administration (United States Public Health Service) and as a neuropsychiatrist at Ellis Island Marine Hospital (1943-1945).

From the mid 1930s to the mid 1950s, Wortis became known for his physiological approaches to psychiatry. With a knowledge of six foreign languages, for many years he wrote an annual review of world literature describing physiological methods of treatment for the American Journal of Psychiatry. As a Socialist and Marxist, Wortis gave popular evening courses at the worker's Jefferson School in Manhattan (ca. 1942-1947) at the same time he led a small group of psychiatrists in founding the Benjamin Rush Society. At the close of World War II, Wortis became active in the newly formed American-Soviet Medical Society. Stuart Mudd, the Society's president, induced Wortis to prepare a comprehensive volume on Soviet psychiatry. His Soviet Psychiatry (1950) was a digest of Soviet psychiatric literature because the political climate at that time did not allow for visits to the Soviet Union. From 1946 until 1952, Wortis served as Assistant Clinical Professor of Psychiatry and Director of the Insulin Treatment Unit at New York University.

In 1953, at the height of the McCarthy era, Senator Jenner's Congressional investigative committee summoned Wortis. The committee was set up ostensibly to investigate "Subversive Influence in the Educational Process." Repeatedly asked if he was a member of the Communist Party, Wortis defied the committee by refusing to answer any questions. However, the political harassment Wortis received both preceding and following the hearings, in his view, made it impossible for him to achieve high academic rank or to attract support for his hospital work or research. During this time, Wortis entered the field of mental retardation. He worked at Brooklyn Jewish Hospital, where he served as Director of the Division of Pediatric Psychiatry from 1950 until 1967. While he was at the Jewish Hospital of Brooklyn, Dr. Wortis established the Solomon Clinic for the Rehabilitation of Mentally Retarded Children.

After a change of political climate in the late 1950's, Wortis began again to receive financial support. In particular, a grant from the National Institute of Mental Health (1958-1964) for the translation of Russian psychiatric literature allowed him to travel to the Soviet Union (ca. 1958-1959). During this period, Wortis rose to prominence in the field of mental health. From 1960 until 1973, Wortis served as Professor of Psychiatry at SUNY Downstate Medical Center (Maimonides) and from 1973 through the 1980s, he served in a variety of research and teaching programs involving special education at SUNY Stony Brook. He also edited the Society of Biological Psychiatry's journal Biological Psychiatry from 1959 through 1992.