Born January 4, 1746, in Byberry, Pennsylvania, Rush began work in 1761 as an apprentice to Dr. Redman, a practicing physician in Philadelphia. Rush's work in Redman's apothecary shop, where he learned the uses of various herbal and botanical home remedies such as calomel, opium, ipecac, mercury, magnesia, laudanum, castor oil, rattlesnake root, and Jesuit's bark, would later become the foundation for Rush's own treatment of illnesses. In 1766, Rush left Redman's practice to study medicine at Edinburgh University. In June of 1768 he received his medical degree, having written his thesis on the digestion of food in the stomach, a work which earned him respect and admiration among the British medical community. On his return to Pennsylvania, Rush became professor of chemistry at the College of Pennsylvania (later the University of Pennsylvania), and as part of his general teaching of medicine there, he incorporated the study of climate, soil, weather conditions, food, manners, and medicines of different countries. 

Rush also believed that "by extending our knowledge of the causes of the diseases of domestic animals, we may add greatly to the certainty and usefulness of the profession of medicine, as far as it relates to the human species. The organization of their bodies, the principles of animal life, and the manner in which the remote and proximate causes of diseases produce their morbid effects, are the same in the human body; and most of the medicines produce in them, and in us, nearly a similar operation" (from a lecture he gave at the College of Pennsylvania). Given such beliefs, Rush's teaching included the study of veterinary science as helpful in understanding the causes and cures of many diseases and the biological similarities of all life. During his career, Rush became one of the most distinguished teachers in America, having taught over 3,000 medical students during four decades. Rush also took a position as one of the senior physicians on the staff at the Pennsylvania Hospital, a position he held until his death in 1813. Rush eventually became one of the most influential doctors in America; in addition, many doctors in Europe and America sought out his advice and medical expertise. Rush exchanged medical data with numerous doctors: Archibald Alexander of Virginia, Ashton Alexander of Baltimore, Edward Gantt of Tennessee, Samuel Garland of Philadelphia, John Gibbons of Delaware, and John Fothergill and Sir John Pringle in England. In the 1780's and 90's, during outbreaks of yellow fever and small pox, Rush became one of the first physicians to implement a form of inoculation for such diseases. He also proposed that their cause was the inhalation of fumes from decaying animal and vegetable matter, suggesting sanitation and quarantine in hospitals to prevent the spread of disease. Rush published his own account of the yellow fever epidemic in his essay, An Account of the Bilious Remitting Yellow Fever, as it appeared in the City of Philadelphia, in the year 1793. 

Despite his distinguished position in the medical profession, much controversy surrounded Rush's use of regular bleedings to cure his patients. He saw the human body as a hydraulic machine made-up of numerous orders of vessels and pipes through which ran a constant motion of different fluids. He believed that the regulation of these fluids was the cure for many ailments and that routine bleedings could restore such regulation. Rush also demonstrated a keen interest in botany and agriculture, exemplified in a letter he wrote to George Washington in 1788: 

I received a small quantity of the mangel wurgel or scarcity root seeds a few days ago from Dr. Lettsom of London. In distributing these seeds among the friends of agriculture in this country, I would have been deficient in duty, and patriotism to have neglected to send a small portion of them to your Excellency with particular account of the method of cultivating--as also--of the great encrease, & useful qualities of this extraordinary vegetable. From an accurate examination of the plant, the botanists have agreed in this as being a mongrel species of the beet. Dr. Lettsom has called it the 'Beta hebrida'. (Letter of April 1788). 

During his lifetime, Rush earned widespread recognition as a pioneer in veterinary science, psychiatry, the study of disease, medical education, preventive and pulmonary medicine. He became a specialist in the treatment of tuberculosis. In addition to his wide ranging medical activities, Rush was an active revolutionary patriot: he served as a member of the Continental Congress, signed the Declaration of Independence, corresponded with leading political and social figures, and was one of the founders of Dickinson College.