Decommissioned once again in 1836, while she underwent remodeling, she was refitted with a light spar deck and declared the flagship of the South Sea Surveying and Exploring Expedition to the Antarctic region.

Though this duty proved relatively uneventful, Vincennes did rescue two grounded English brigs off the coast of Texas and received the thanks of the British government for this service.

She was accompanied by the ship-of-the-line Columbus, under the command of Captain Thomas Wyman; and the two vessels formed a little squadron under the command of Commodore James Biddle, who carried a letter from Secretary of State John C. Calhoun to Caleb Cushing, American commissioner in China, authorizing Cushing to make the first official contact with the Japanese Government.

Commodore Biddle arrived safely in Macau only to find that Cushing had already left for home and that his successor, Alexander H. Everett, was too ill to make the trip.

However, Commodore Biddle's attempts to force the opening of feudal Japan to multinational trade were politely rebuffed, and the vessels weighed anchor on 29 July.

On 2 July 1850, while lying off Guayaquil, Ecuador, she harbored the Ecuadoran revolutionary General Elizalde for three days during one of that country's frequent civil disturbances.

Following repairs and a period in ordinary, Vincennes was recommissioned on 21 March 1853 and sailed into Norfolk, Virginia on 13 May to join her second exploratory expedition, serving as flagship to Commander Cadwalader Ringgold's survey of the China Sea, the North Pacific, and the Bering Strait.

The squadron stood out of Norfolk on 11 June 1853, rounded the Cape of Good Hope, and charted numerous islands and shoals in the Indian Ocean before arriving in China in March 1854.

Here Commodore Matthew Calbraith Perry relieved Ringgold for medical reasons and gave command of the expedition to Lt. John Rodgers.

Vincennes returned to San Francisco in early October and later sailed for the Horn and New York, where she arrived on 13 July 1856 to complete yet another circumnavigation of the globe.

After the outbreak of the American Civil War in April 1861, Vincennes was recommissioned on 29 June and assigned to duty in the Gulf Blockading Squadron.

She arrived off Fort Pickens, Florida, on 3 September, and was ordered to assist in the occupation of Head of Passes, Mississippi River, and remain there on blockade duty.

Vincennes was ordered abandoned and destroyed to prevent her capture, and her engineer set a slow match to the vessel's magazine while her men took refuge on other ships.

However, her engineer cut the burning fuse and threw it overboard before the magazine could explode and, after the Confederate vessels withdrew early in the afternoon, Vincennes was refloated.