ilkinson was born in Benedict, Maryland, in 1757. He studied medicine at the University of Pennsylvania and opened a medical practice in Maryland. During the Revolution, he served as aide-de-camp to General Horatio Gates and carried the news of America's victory at Saratoga to Congress. Wilkinson's indiscreet criticism of General Washington's authority forced his reassignment to administrative duty as clothier general, in which post he served until 1781. Three years later, he moved to the Virginia frontier, where he promoted the territory's reorganization as the new state of Kentucky. At that time, he secretly advised the Spanish government on American plans for western development, receiving a sizable annual pension and favored trading status for his cooperation.

n 1791, Wilkinson returned to military duty during the Ohio River Territory Indian campaigns, succeeding General Anthony Wayne. As military governor of the southwest territory, Wilkinson participated in the 1803 transfer of the Louisiana Purchase from France to the United States. He served briefly as governor of the vast new territory. He was publicly criticized for his heavy-handed administration and reassigned to frontier military duty. Public concerns about his abuse of authority increased when Wilkinson's participation in former vice president Aaron Burr's scheme to establish an independent western nation was revealed. He narrowly escaped indictment during Burr's treason trial, and was twice investigated by Congress. Following an unsuccessful court-martial, he returned to his military command in New Orleans.

ith the outbreak of renewed war between America and England in 1812, Wilkinson was posted to Canada. His major offensive against the British in Montreal failed, and he was discharged from active service. Wilkinson died in Mexico on 28 December 1825.