Francis Blair was born on February 19, 1821, in Lexington, Kentucky. He attended schools in Washington, D.C., graduated from Princeton University in 1841, and studied law at Transylvania University. After his admission to the bar in Lexington, he went on to practice in St. Louis in 1842.

Blair participated in the Mexican War and was appointed attorney general for the New Mexican Territory after it was secured by General Kearny. A personal and political friend of Thomas Hart Benton, he became known for his views opposing slavery. He also was an outspoken Free-Soiler and was elected to the U.S. House of Representatives in 1852. He was defeated in 1858 but reelected in 1860. In 1861 he was instrumental in saving Missouri for the Union. He served as a major general in the United States Army during the Civil War.

At the close of the war, Blair, having spent much of his private fortune in support of the Union, was financially ruined. He was the unsuccessful Democratic candidate for vice president in 1868, but he was chosen by the Missouri Legislature as a United States Senator in 1871. He was defeated for reelection in 1873. During the same year he was stricken with paralysis, from which he never recovered. Blair died on July 9, 1875.