Cockrell was born in Warrensburg, Missouri. His older brother was Jeremiah Vardaman Cockrell who was a congressman from Texas in the 1890s. Francis Cockrell attended local schools and became a lawyer as a young man, practicing law in Warrensburg. At the beginning of the American Civil War in 1861, Cockrell joined the Confederate Army as a captain. He eventually rose to the rank of brigadier general and was an important leader in the Vicksburg campaign. In April 1865, shortly before the end of the war which resulted in defeat for the Confederates, Cockrell was captured in Alabama but paroled after a few weeks. He returned to his law practice in Missouri.

In 1874, Cockrell, who became a member of the United States Democratic Party was elected to the United States Senate from Missouri by the state legislature. He served in the Senate from 1875 to 1905 when he retired. He held several committee chairmanships, including the chairmanships of the Claims Committee, Engrossed Bills Committee and Appropriations Committee during his senate career.

He was appointed to the Interstate Commerce Commission by President Theodore Roosevelt in 1905. He served on the Commission until 1910. Cockrell then became part of a commission which negotiated the boundaries between the state of Texas and the territory of New Mexico which was about to become a state. In 1912 he became a director of ordnance at the War Department. He remained in that job until his death. He died in Washington, D.C.