The first Lancaster was laid down by the Philadelphia Navy Yard in December 1857; launched 20 October 1858; sponsored by Miss Harriet Lane, niece and official hostess of President James Buchanan; and commissioned 12 May 1859, Captain John Rudd in command.

On 23 February, Rear Admiral Charles H. Bell reported an incident which typified her service during the Civil War: "Such is the present state of affairs at Acapulco, that it is believed by both native and foreign populations that the presence of man-of-war alone prevented an attempt to sack and destroy the town by the Indians in the interior, encouraged by governor, General Alvarez ..." Far from the main theaters of the Civil War, a U.S. naval vessel was carrying out the traditional mission of protecting U.S. interests and keeping the peace.

On 11 November 1864, a secret expedition of boats from the ship captured a party of Confederate officers aboard the passenger steamer Salvador, off the Bay of Panama.

In the spring of 1866, Lancaster received extensive repairs at the Mare Island Navy Yard and on 27 June sailed from San Francisco, California for the east coast, via Panama Bay, Callao, Valparaíso, Barbados, and Nassau.

From January to May 1874, she took part in fleet drills in the North Atlantic and was in the force concentrated at Key West lest war with Spain break out over the "Virginius affair".

After diplomatic efforts resolved the controversy peacefully, Lancaster returned to the South Atlantic until she departed Rio de Janeiro on 21 May 1875 for home, arriving at Portsmouth, New Hampshire, 12 July.

Acting under instructions from the Navy Department, Admiral Baldwin proceeded in Lancaster to Kronstadt, Russia, and on 27 May he and his staff attended the coronation of Tsar Alexander III at Moscow.

On 20 November 1883, while Lancaster was in port in Marseille, France, a young Frenchman who was on a stone pier astern of the ship fell overboard, and disappeared below the water twice.

As flagship of the European Squadron she cruised in the Mediterranean until she departed Gibraltar 2 July 1889 and returned to the United States via Funchal, Madeira, arriving at New York 8 August.

From 3 June 1900 to 4 March 1901 she made a cruise to European waters, returning to the United States via the West Indies and La Guaira, Venezuela.

Lancaster served as receiving ship at the Philadelphia Navy Yard, 16 November 1903 to 31 March 1912, and was transferred to the Treasury Department's Bureau of Public Health Service, on 1 February 1913.