[4] In 1853, Clay was elected by the Alabama legislature to serve in the United States Senate in a term beginning March 4, 1853; and was re-elected in 1857.

He described the election of Abraham Lincoln to the presidency as a hostile act against the Southern people which left them with no recourse other than secession in order to defend their liberty, honor, and safety.

[citation needed] Along with Jacob Thompson, Clay was a part of the Confederate War Department effort to create a network of secret agents to conduct espionage and sabotage.

[7] In May 1864, president Davis sent Clay to Canada with a secret mission to coordinate activities of the Southern sympathizers in the Great Lakes area, including members of the Order of the Sons of Liberty and the Knights of the Golden Circle.

[8] Clay took part in a secret meeting with John Hay, President Abraham Lincoln's aide, at Niagara Falls, Canada.

[9] It was suspected that Thompson and Clay had employed John Wilkes Booth for some services before he assassinated President Abraham Lincoln.

After learning from a newspaper that a reward was issued for his capture, Clay, who initially planned to escape to Mexico, turned himself in to General James H. Wilson in Macon, Georgia, in May 1865.

Clay was imprisoned by the United States government under impression that he was involved in the plot to assassinate President Abraham Lincoln.

Clay tried to practice as an attorney and entered insurance business in Huntsville, however without much success due to poor health, ultimately returning to his farm in January 1882.

He died later that year in Madison County, besieged by debts and health problems, and is interred at Maple Hill Cemetery.