Water Witch was launched by the Washington Navy Yard in 1851 and was commissioned during the winter of 1852–53, Lieutenant Thomas Jefferson Page in command.

On 8 February 1853, the gunboat set sail from Norfolk, Virginia, for an extended exploration and survey voyage along the Atlantic coast of the southern portion of South America and of the rivers which drain that part of the continent.

In January 1859, Water Witch and Fulton arrived in Asunción, the capital of Paraguay; and, backed by the warships, an American commissioner, James B. Bowlin, began negotiations with the Paraguayans.

She returned to active duty on 10 April 1861, just two days before General Beauregard's bombardment of Fort Sumter opened hostilities between the North and the South.

On 5 March 1862, the gunboat pursued the Confederate schooner, William Mallory, for five hours before finally capturing the blockade runner late in the day.

On 6 September, she was recommissioned and ordered to join Rear Admiral Samuel F. du Pont's South Atlantic Blockading Squadron.

She arrived at Port Royal, South Carolina, on 18 September and, by the end of the month, was on blockade station in the St. Johns River in northeastern Florida.

On the night of 3 June of that year, a Confederate Marine boat force under the command of First Lieutenant Thomas P. Pelot, CSN, succeeded in boarding and capturing Water Witch in Ossabaw Sound after a brief scuffle which cost the Union ship two killed and 12 wounded.

Plans were being made to move her to Savannah for some special assignment, but she remained at White Bluff, Georgia, until 19 December 1864 when the Confederates burned her to prevent recapture.

In 2009, the National Civil War Naval Museum completed construction of a full-scale reproduction of the USS Water Witch using her original plan drawings at their facilities in Columbus, Georgia.

The museum's Water Witch recreation and exhibit was on display for visitors until October 2019, by which time the reproduction had deteriorated from weathering and was demolished.