The city of Wickliffe is the site of a Mississippian culture village now known only as Wickliffe Mounds. The village was occupied from around 1100-1300 AD. Today, Wickliffe Mounds is a state historic site and home to a research center and museum.
In 1780 during the Revolutionary War, General George Rogers Clark established Fort Jefferson on a hill overlooking the Mississippi River one mile south of present-day Wickliffe. The fort was intended to protect what was then the western boundary of the infant United States from raids by the British Army and Native Americans. It was abandoned in 1781 after a siege by the Chickasaw.
The site later served as a Union Army post during the Civil War. General Ulysses S. Grant directed a demonstration against the Confederate-held position at Columbus, Kentucky, in January 1862. Troops from the post joined in capturing Fort Henry in February 1862. It served as a Union supply post for operations in the western theater of the war.
A cross, the Fort Jefferson Memorial Cross at the Confluence, was completed in 2000 on Fort Jefferson hill.