In 1833, for his survey of Narragansett Bay, he was placed in charge of the Navy's Department of Charts and Instruments, out of which developed the Naval Observatory and Hydrographic Office. Wilkes interdisciplinary expedition (1838-1842) set a physical oceanography benchmark for its first superintendent Matthew Fontaine Maury.
The United States Exploring Expedition, commonly known as the Wilkes Expedition, included naturalists, botanists, a mineralogist, taxidermists, artists and a philologist, and was carried by the USS Vincennes (780 tons) and Peacock (650 tons), the brig Porpoise (230 tons), the store-ship Relief, and two schooners, Sea Gull (110 tons) and Flying Fish (96 tons).
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 Fiji and the Hawaiian Islands in 1840, explored the west coast of the United States, including the Strait of Juan de Fuca, Puget Sound, 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.
In July 1840, two sailors, one of whom was Wilkes' nephew, Midshipman Wilkes Henry, were killed while bartering for food on Fiji's Malolo Island. Wilkes retribution was swift and severe. According to an old man of Malolo Island, nearly 80 Fijians were killed in the incident.
After having completely encircled the globe (his was the last all-sail naval mission to do so), Wilkes had logged some 87,000 miles and lost two ships and 28 men. Wilkes was court-martialled on his return for the loss of one of his ships on the Columbia River bar, for the regular mistreatment of his subordinate officers, and for excessive punishment of his sailors. He 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.
His Narrative of the United States Exploring Expedition (5 volumes and an atlas) were published in 1844. He edited the scientific reports of the expedition (20 volumes and 11 atlases, 1844–1874) and was the author of Vol. XI (Meteorology) and Vol. XIII (Hydrography).
The Narrative contains much interesting material concerning the manners and customs and political and economic conditions in many places then little known. Wilkes's 1841 Map of the Oregon Territory pre-dated John Charles Fremont's first Oregon Trail pathfinder expedition guided by Kit Carson during 1842.
Other valuable contributions were the three reports of James Dwight Dana on Zoophytes (1846), Geology (1849) and Crustacea (1852-1854). Moreover, the specimens and artifacts brought back by expedition scientists ultimately formed the foundation for the Smithsonian Institution collection. In addition to many shorter articles and reports, Wilkes published the major scientific works Western America, including California and Oregon in 1849, and Theory of the Winds in 1856.
As part of these duties, he visited the British colony of Bermuda. Acting on his orders, however violating the British rule that allowed American naval vessels (of either side) to remain in port for a single day, Wilkes remained in port for nearly a week aboard his flagship the Wachusett, while his gunboats Tioga and Sonoma blockaded St. George harbour, a key Confederate blockade-runner base. The gunboats prevented a number of ships from leaving the harbour, and opened fire at a Royal Mail Steamer, the Merlin. The actions of "The Notorious Wilkes"—as local media branded him—convinced many that full-scale war between the United States and the United Kingdom was inevitable, though the British government had no wish to enjoin the conflict between the Union and Confederacy.
In addition to his contribution to U.S. Naval history and scientific study in his official Narrative of the Exploration Squadron (6 volumes), Wilkes also authored an autobiography.
Wilkes died in Washington, D. C. on February 8, 1877 with the rank of Rear Admiral.
In August 1909, the United States paid its final tribute to Rear Admiral Wilkes by moving his remains to Arlington National Cemetery.