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 the office's first superintendent Matthew Fontaine Maury.

[5] Departing from Hampton Roads on August 18, 1838, the expedition 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" of which it sighted the coast on January 25, 1840.

From December 1840 to March 1841, he employed hundreds of native Hawaiian porters and many of his men to haul a pendulum to the summit of Mauna Loa to measure gravity.

[13] The expedition 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.

[6] After having completely encircled the globe as 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-martialed upon 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.

In addition to many shorter articles and reports, Wilkes published the major scientific works Western America, including California and Oregon in 1849 and Voyage round the world: embracing the principal events of the narrative of the United States Exploring Expedition in one volume: illustrated with one hundred and seventy-eight engravings on wood in 1849, and Theory of the Winds in 1856.

At the outbreak of the American Civil War, he was assigned to the command of USS San Jacinto to search for the Confederate commerce destroyer CSS Sumter.

When Wilkes learned that James Murray Mason and John Slidell, two Confederate commissioners (to Britain and France, respectively), were bound for England on a British packet boat, RMS Trent, he ordered the steam frigate San Jacinto to stop them.

A party from San Jacinto led by its captain then boarded Trent and arrested Mason and Slidell, a further violation of British neutrality.

The actions of "The Notorious Wilkes," as Bermuda media branded him, were contrary to maritime law and convinced many that full-scale war between the United States and England was inevitable.

He also repeatedly exacerbated diplomatic relations with the British, Spanish, Dutch, French, Danes and Mexicans through his arrogant and illegal activities in the West Indies and Bermuda.

His failure to capture the Confederate commerce raiders certainly played a role, and his retention of the USS Vanderbilt in direct contravention of explicit orders to release it to independently hunt the Alabama served as a justification, but he probably owed his removal primarily to the seeming never-ending stream of complaints from neutral nations over his actions.

[20] Though supported by him in many of his actions in the West Indies, Wilkes frequently found himself in open conflict with Secretary of the Navy Gideon Welles.

[6] One historian speculated that Wilkes' obsessive behavior and harsh code of shipboard discipline shaped Herman Melville's characterization of Captain Ahab in Moby-Dick.

In addition to his contribution to United States naval history and scientific study in his official Narrative of the Exploration Squadron (6 volumes), Wilkes wrote his autobiography.