Portsmouth had an important role during the Mexican–American War, seizing the port of Yerba Buena (today's San Francisco) from Mexico.

[1] She had set sail on 25 January 1845 from Norfolk, Virginia, on a cruise around Cape Horn to join the Pacific Squadron under the command of Commodore John D. Sloat.

Hunter as her Sailing Master, she was initially engaged in watching the movements of British vessels there to prevent the possibility of Great Britain acquiring the region during any conflict between the U.S. and Mexico.

[citation needed] After the declaration of war with Mexico, a detachment of Marines under the command of Second Lieutenant Henry Bulls Watson rowed ashore on 9 July 1846, marched to the pueblo's main plaza, and raised the American flag, thereby seizing the city.

Ship's surgeon William H. Jones performed a survey of the animal and plant life, as well as creating a detailed map of the atoll's islets and lagoons.

[3] In 1875 she conducted a cruise off the west coast of Latin America and on 14 July 1878 was decommissioned as a cruiser and assigned as a training ship for boys.

On 25 July 1876 at Mare Island Naval Shipyard, Boatswain's Mate Alexander Parker attempted to rescue a shipmate from drowning, for which he was later awarded a Medal of Honor.

Portsmouth was then loaned to the Public Health Service, Quarantine Station, Charleston, South Carolina to serve as a boarding launch.

The Portsmouth was adopted as the logo for the San Francisco-founded Bank of America by its founder, Amadeo Giannini, in recognition of the ship's role in securing the city.