Wilkes was born in New York City. He entered the United States Navy as a midshipman in 1818, and became a lieutenant in 1826. In 1830 he was placed in charge of the division of instruments and charts, and in 1838 was appointed to command an exploring and surveying expedition in the Southern Seas, authorized by Congress in 1836. The expedition, including naturalists, botanists, a mineralogist, taxidermists and a philologist, was carried by the sloops-of-war "Vincennes" and "Peacock", the brig "Porpoise", the store-ship "Relief" and two tenders.
Leaving Hampton Roads on August 18, 1838, it stopped at the Madeira islands and Rio de Janeiro; visited Tierra del Fuego, Chile, Peru, the Tuamotu Archipelago, Samoa and New South Wales; from Sydney sailed into the Antarctic Ocean in December 1839 and reported the discovery 'of an Antarctic continent west of the Balleny Islands'; visited the Fiji and the Hawaiian islands in 1840, explored the west coast of the United States, including the Columbia river, San Francisco Bay and the Sacramento River, in 1841, and returned by way of the Philippines, the Sulu Archipelago, Borneo, Singapore, Polynesia and the Cape of Good Hope, reaching New York on June 10, 1842.
Wilkes was court-martialled on his return, but was acquitted on all charges except that of illegally punishing men in his squadron. For a short time he was attached to the Coast Survey, but from 1844 to 1861 he was chiefly engaged in preparing the report of the expedition. Twenty-eight volumes were planned but only nineteen were published. Of these Wilkes wrote the Narrative (1845) and the volumes Hydrography and Meteorology (1851). The Narrative contains much interesting material concerning the manners and customs and political and economic conditions in many places then little known. Other valuable contributions were the three reports of James Dwight Dana on Zoophytes (1846), Geology (1849) and Crustacea (1852-1854).
At the outbreak of the American Civil War, Wilkes (who had reached the rank of commander in 1843 and that of captain in 1855) was assigned to the command of the " San Jacinto " to search for the Confederate commerce destroyer, "Sumter." On November 8, 1861 he stopped the British mail packet " Trent," and took off the Confederate commissioners to Europe, James Murray Mason and John Slidell. Though he was officially thanked by Congress, his action was later disavowed by President Lincoln. His next service was in the James River flotilla, but after reaching the rank of commodore, on July 16, 1862, he was assigned to duty against blockade runners in the West Indies.
He was disrated (becoming a captain on the retired list) in November 1862 on the ground that he had been too old to receive the rank of commodore under the act then governing promotions; and engaged in a long controversy with Gideon Welles, secretary of the navy. This controversy ended in his being court-martialled in 1864 and being found guilty on several counts and sentenced to public reprimand and suspension for three years. But on July 25, 1866 he was promoted to the rank of rear-admiral on the retired list. He died at Washington.
In addition to many shorter articles and reports, he published Western America, including California and Oregon (1849) and Theory of the Winds (1856).