Born in Byberry, Pennsylvania, near Philadelphia. His father died when he was young and he was raised by his maternal uncle Dr. Finley. He obtained a Bachelor of Arts degree at the College of Philadelphia, and then obtained an M.D. degree at Edinburgh. While in Europe practicing medicine, he learned French, Italian, and Spanish. Returning to America in 1769, he opened a medical practice at Philadelphia, and became Professor of Chemistry at the College of Philadelphia.
He published the first American textbook on Chemistry, and wrote influential patriotic essays. He was active in the Sons of Liberty and was elected to attend the provincial conference to send delegates to the Continental Congress. He was appointed to represent Pennsylvania ad signed the Declaration of Independence..
In 1777 he became surgeon-general of the middle department of the Continental Army. Conflicts with the Army Medical service, specifically with Dr. William Shippen, led to Rush's resignation.
As General George Washington suffered a series of defeats in the war, Rush campaigned for his removal, losing his trust and ending Rush's war activities.
He was elected to the Pennsylvania convention which adopted the Federal constitution, and was appointed treasurer of the U.S. Mint, serving from 1797-1813.
He became Professor of medical theory and clinical practice at the University of Pennsylvania in 1791, though the quality of his medicine was quite primitive even for the time: he advocated bleeding (for almost any illness) long after its practice had declined. He became a social activist, and abolitionist, and was the most well-known physician in America at the time of his death.