He was born in Calvert County, Maryland, the second son of a respected Maryland merchant-planter. He received his early education from a private tutor and his study of medicine in Philadelphia at the University of Pennsylvania was interrupted by the American revolution.

Revolutionary war actions

He first served in Thompsons Pennsylvania rifle battalion, 17751776, and was commissioned a Captain in September 1775. He served under Colonel Benedict Arnold in the Siege of Boston and at Montreal during the Invasion of Canada (1775). He became an aide to General Horatio Gates in early 1776 and served under General George Washington in the battles at Trenton and Princeton. He was brevetted as Major General from November 1777 to March 1778, and was concurrently secretary to the Board of War, January to March 1778.

During the revolutionary war, he was a participant in the Conway Cabal, a conspiracy to replace George Washington with Horatio Gates as commander-in-chief of the Continental Army. Because of this, he was forced to resign his positions as brevet Major General and secretary. He then served as clothier general of the Army from July 1779 to March 1781.

Kentucky ventures

He resigned from the army amid accusations of corruption. He became Brigadier General of the Pennsylvania militia in 1782 and state assemblyman in 1783. He moved to the Kentucky District in 1784 and was active there in efforts to achieve independence from Virginia.

In 1787, Wilkinson undertook a highly controversial trip to New Orleans, then a colony of Spain. At that time, Americans were not allowed to trade in New Orleans. Wilkinson met with the Spanish Governor Esteban Rodriguez Miro and managed to convince him to allow Kentucky to have a trading monopoly over trade on the Mississippi River; in return he promised to promote Spanish interests in the west. In August 1787, Wilkinson signed an expatriation declaration, and swore allegiance to the King of Spain.

Upon returning to Kentucky in February 1788, Wilkinson vigorously opposed the new U.S. Constitution. Kentucky had very nearly achieved statehood under the old Articles of Confederation and there was widespread disappointment when this was delayed due to the new constitution.

Leading up to Kentucky's seventh convention regarding separation from Virginia in November 1788, Wilkinson attempted to gauge the support for Kentucky to seek union with Spain. At the convention, Wilkinson was elected chair, and he advocated seeking independence from Virginia first, and then consider joining the Union of states as a second step. For many, joining the Union was conditional upon the Union negotiating free navigation on the Mississippi with Spain, a contentious point about which many Kentuckians doubted the eastern states would act upon.

Unable to gather enough support for his position at the convention, Wilkinson instead took his own initiative and approached Miro with a proposal to grant them 60,000 acres (243 km) in the Yazoo lands at the junction of the Yazoo River and the Mississippi (near present-day Vicksburg, Mississippi). The land was to be payment for Wilkinson's efforts on behalf of Spain and also to serve as a refuge in the event he and his supporters had to flee from the United States. Wilkinson asked for and received a pension of $7,000 from Miro and also requested pensions on behalf of a number of prominent Kentuckians, including: Harry Innes, Benjamin Sebastian, John Brown, Caleb Wallace, Benjamin Logan, Isaac Shelby, George Muter, George Nicholas, and even Humphrey Marshall (who at one time was a bitter rival of Wilkinson's).

However, by 1788 Wilkinson had apparently lost the support of officials in the Spanish mainland. Miro was not to grant any of the proposed pensions and was forbidden from giving money to support revolution in Kentucky. However, Wilkinson continued to secretly receive funds from Spain for many years.

Second Military Career

In March 1791, he led a force of Kentucky volunteers against Indians north of the Ohio River, and in October he received a commission to the U.S. Army as lieutenent colonel, commandant of the 2nd Infantry. He was promoted to Brigadier General and served on the frontier under General Anthony Wayne, commanding the right wing in the Battle of Fallen Timbers in August 1794. During this time, he secretly maintained contacts with the Spanish government and informs them of plans for General George Rogers Clark to attack New Orleans in 1793-1794. He was appointed commander at Detroit in 1796 and partially redeemed himself by rejecting entreaties to lead a rebellion in the Natchez, Mississippi area. Despite his treachery, upon Wayne's death, he became the senior officer of the U.S. Army from December 15, 1796 to July 13, 1798.

Wilkinson was transferred to the southern frontier in 1798 and was designated to treat with the regional Indian tribes. He was again the senior officer of the United States Army, from June 15, 1800 to January 27, 1812. Along with Governor William C. C. Claiborne, he shared the honor of taking possession of the Louisiana Purchase on behalf of the United States in 1803.

In 1804-1805, he exchanged communications with Aaron Burr, which many suspect concerned Burr's conspiracy to set up an independent nation in the west. Some embittered associates later claim that Wilkinson was the mastermind behind the plot for which Burr was accused. In 1805, U.S. President Thomas Jefferson appointed Wilkinson as the first governor of the newly organized Louisiana Territory. He was removed from this office after being publicly criticized for heavy-handed administration and abuse of power. Perhaps in an attempt to save himself, he betrayed Burr's plans to Thomas Jefferson. Wilkinson testified at Burr's trial, resulting in public accusations against him and two congressional inquiries of his private ventures and intrigues. President James Madison ordered his court martial in 1811. He was found not guilty on December 25, 1811.

Wilkinson was commissioned a major general in the War of 1812 and in March 1813, Wilkinson and his soldiers occupied Mobile, Alabama in what was then Spanish West Florida. He was then assigned to the St. Lawrence River sector, after Henry Dearborn's reassignment. He led two failed campaigns (Battle of Chrysler's Farm and Battle of La Colle Mill) and was relieved from active service, but he was cleared by a military inquiry. He published his memoirs, Memoirs of My Own Times, in 1816 and visited Mexico in pursuit of a Texas land grant in 1821. While waiting for Mexican approval of his Texas scheme, Wilkinson died in Mexico City where he was also buried.

Wilkinson's Spanish involvement, although suspected, was not proven until long after his death following research in Spanish archives.

Wilkinson married Ann Biddle of the famous Biddle family, in 1778 and had four children with her. After Ann's death on March 5, 1810, he married Celeste Laveau Trudeau, with whom he had two children.