USS Powhatan's keel was laid on 6 August 1847 at Norfolk, Virginia. Her engines were constructed by Mehaffy & Company of Gosport, Virginia. She was launched on 14 February 1850.
She was initially assigned as flagship of the Home Squadron and served in that capacity for two years.
During the period 1852 to 1854 Powhatan served in the East India Squadron. She was a participant in Commodore Matthew Perry's expedition to Japan. The Treaty of Kanagawa was signed on her deck on 31 March 1854.
In the summer of 1855 she was reassigned and enroute back to the United States she joined with the Royal Navy's HMS Rattler in a mission against pirates in the Pacific.
In 1857 the Powhatan joined the West Indies Squadron.
The Powhatan served during the American Civil War. In 1861 under the command of Lieutenant David Dixon Porter she took part in the relief of Fort Pickens, Florida and assisted in establishing blockades off of Mobile, Alabama and the Gulf coast of Mississippi.
In 1863 and 1864 she operated with the West Indies Squadron off of the coast of Charleston, South Carolina.
In the winter of 1864 she took part in the reduction of Fort Fisher, North Carolina.
After the war Powhatan served as the flagship of Rear Admiral John A. Dahlgren in the South Pacific.
In 1869 she was assigned to the Home Squadron and remained in the Atlantic Ocean for the rest of her career.
USS Powhatan was decommissioned in 1886, was sold on 30 July 1887, and was broken up that same year in Meriden, Connecticut.