He was educated as a lawyer and married Anna Tuthill (1741-1776) at Mattituck, New York on October 30, 1760. They had two children; Maria (born April 23, 1765) and Mary (born August 30, 1767) at Mattituck before moving to New Jersey sometime around 1770. Another daughter Anna Tuthill Symmes was born in 1775 near Morristown, before his wife died in 1776.
He supported the revolution, becoming chairman of the Sussex County, New Jersey Committee of Safety in 1774. When the Revolutionary war began in earnest, he served as Colonel of the 3rd Regiment of the Sussex County militia from 1777 to 1780. The unit was called into service with the Continental Army on several actions.
He served on the New Jersey state supreme court in 1777 and 1778. Then in 1778 Governor William Livingston appointed him to the state council. He was a frequent visitor to the Governor both in Elizabethtown and in Parsippany. In 1779 John married his daughter, Susannah Livingston. Besides being the governor's daughter, she was John Jay's sister-in-law.
He represented New Jersey in the Continental Congress (1785-1786), then in 1788 moved to the west, settling in what later became North Bend, Ohio. He served as a judge of the Territorial Court from 1788 until Ohio became a state in 1803. He also pursued an active career as a land developer and seller. He died on February 26, 1814 at Cincinnati, Ohio, and is buried at North Bend.
Symmes bought 330,000 acres from the Congress in 1788. President George Washington signed the U.S. Patent (deed) on September 30, 1794 conveying to Symmes 248,250 acres plus a surveying township (23,040 acres), in trust, for an academy. This land was known as the Symmes Purchase, and was the cause of considerable controversy in his lifetime and after. The purchase price was $225,000, and was paid in notes issued by the Congress to raise money during the war.
There is no doubt that a considerable part of this amount came from Symmes in the first place as he lent most of his own money to the revolution.
There were other investors who served as partners in the transaction. There is also no doubt that some of these notes were purchased from other holders, probably at a discount. This was before the rampant speculation in these notes that happened a few years later, but is still questionable.
There were also disputes about the actual boundaries of the purchase and the quality of surveying and validity of titles. In the last years of his life he spent a lot of time in court, defending himself from claims.