In 1809, Perry received a midshipman’s warrant in the Navy, and was initially assigned to USS Revenge, under the command of his elder brother. His early career saw him assigned to several ships, including USS President, where he served as an aide to Commodore John Rodgers. President was in a victorious engagement over a British vessel, HMS Little Belt, shortly before the War of 1812 was officially declared. Perry continued aboard President during the War of 1812 and was present at the engagement with HMS Belvidera. Rodgers fired the first shot of the war at Belvidera. A later shot resulted in a cannon bursting, killing several men and wounding Rodgers, Perry and others. Perry transferred to USS United States, commanded by Stephen Decatur, and saw little fighting in the war afterwards, since the ship was trapped in port at New London, Connecticut.

In 1815 the Spanish governor in Havana deeded the island of Key West to Juan Pablo Salas of Saint Augustine. After Florida was transferred to the United States, Salas sold Key West to American businessman John W. Simonton for $2,000 in 1821. Simonton lobbied Washington to establish a naval base on Key West both to take advantage of its strategic location and to bring law and order to the area. On March 25, 1822, Perry sailed Shark to Key West and planted the U.S. flag, physically claiming the Keys as United States territory. Perry renamed Cayo Hueso “Thompson’s Island” for the Secretary of the Navy Smith Thompson and the harbor “Port Rodgers” for the president of the Board of Navy Commissioners. Neither name stuck however.

From 1826 to 1827, Perry acted as fleet captain for Commodore Rodgers. Perry returned to Charleston, South Carolina for shore duty in 1828, and in 1830 took command of a sloop-of-war, USS Concord. He spent the years 1833–1837 as second officer of the New York Navy Yard (later the Brooklyn Navy Yard), gaining promotion to captain at the end of this tour.

Perry received the title of commodore in June 1840, when the Secretary of the Navy appointed him commandant of New York Navy Yard. The United States Navy did not have ranks higher than captain until 1857, so the title of commodore carried considerable importance. Officially, an officer would revert to his permanent rank after the squadron command assignment had ended, although in practice officers who received the title of commodore retained the title for life, as did Perry.

During his tenure in Brooklyn, he lived in Quarters A in Vinegar Hill, a building which still stands today. In 1843, Perry took command of the African Squadron, whose duty was to interdict the slave trade under the Webster-Ashburton Treaty, and continued in this endeavor through 1844.

In 1845, Commodore David Conner’s length of service in command of the Home Squadron had come to an end. However, the coming of the Mexican–American War persuaded the authorities not to change commanders in the face of the war. Perry, who would eventually succeed Conner, was made second-in-command and captained USS Mississippi. Perry captured the Mexican city of Frontera, demonstrated against Tabasco, being defeated in San Juan Bautista by Colonel Juan Bautista Traconis in the First Battle of Tabasco, and took part in the capture of Tampico (November 14, 1846). He had to return to Norfolk, Virginia to make repairs and was still there when the amphibious landings at Veracruz took place. His return to the U.S. gave his superiors the chance to finally give him orders to succeed Commodore Conner in command of the Home Squadron. Perry returned to the fleet during the siege of Veracruz and his ship supported the siege from the sea. After the fall of Veracruz, Winfield Scott moved inland and Perry moved against the remaining Mexican port cities. Perry assembled the Mosquito Fleet and captured Tuxpan in April 1847. In July 1847 he attacked Tabasco personally, leading a 1,173-man landing force ashore and attacking the city of San Juan Bautista (Villahermosa today) from land defeating the Mexican forces and taking the city.

In 1852, Perry was assigned a mission by American President Millard Fillmore to force the opening of Japanese ports to American trade, through the use of gunboat diplomacy if necessary. The growing commerce between the United States and China, the presence of American whalers in waters offshore Japan, and the increasing monopolization of potential coaling stations by the British and French in Asia were all contributing factors. Shipwrecked foreign sailors were either imprisoned or executed, and the safe return of such persons was one demand. The Americans were also driven by concepts of Manifest Destiny and the desire to expand western civilization to what they perceived as more backward Asian nations. The Japanese were forewarned by the Dutch of Perry’s voyage, but were unwilling to change their 250-year-old policy of national seclusion. There was considerable internal debate in Japan on how best to meet this potential threat to Japan’s economic and political sovereignty.

On November 24, 1852, Perry embarked from Norfolk, Virginia for Japan, in command of the East India Squadron in pursuit of a Japanese trade treaty. He chose the paddle-wheeled steam frigate Mississippi as his flagship, and made port calls at Madeira (December 11–15), St Helena (January 10–11), Cape Town (January 24 – February 3), Mauritius (February 18–28), Ceylon (March 10–15), Singapore (March 25–29) and Macao and Hong Kong (April 7–28), where he met with American-born Sinologist Samuel Wells Williams, who provided Chinese language translations of his official letters, and where he rendezvoused with Plymouth. He continued to Shanghai (May 4–17), where he met with the Dutch-born American diplomat, Anton L. C. Portman, who translated his official letters into the Dutch language, and where he rendezvoused with Susquehanna.

Perry finally reached Uraga at the entrance to Edo Bay in Japan on July 8, 1853. His actions at this crucial juncture were informed by a careful study of Japan’s previous contacts with Western ships and what he knew about the Japanese hierarchical culture. As he arrived, Perry ordered his ships to steam past Japanese lines towards the capital of Edo, and turn their guns towards the town of Uraga. Perry refused Japanese demands to leave, or to proceed to Nagasaki, the only Japanese port open to foreigners.

In the meantime, the Japanese government was paralyzed due to the incapacitation by illness of shōgun Tokugawa Ieyoshi and by political indecision on how to handle the unprecedented threat to the nation’s capital. On July 11, Rōjū Abe Masahiro bided his time, deciding that simply accepting a letter from the Americans would not constitute a violation of Japanese sovereignty. The decision was conveyed to Uraga, and Perry was asked to move his fleet slightly southwest to the beach at Kurihama (in modern-day Yokosuka), where he was allowed to land on July 14, 1853. After presenting the letter to attending delegates, Perry departed for Hong Kong, promising to return the following year for the Japanese reply.

Perry returned on 13 February 1854, after only half a year rather than the full year promised, and with ten ships and 1600 men. Both actions were calculated to put even more pressure onto the Japanese. After initial resistance, Perry was permitted to land at Kanagawa, near the site of present-day Yokohama on March 8, 1854, where, after negotiations lasting for around a month, the Convention of Kanagawa was signed on March 31, 1854. Perry signed as American plenipotentiary, and Hayashi Akira, also known by his title of Daigaku-no-kami, signed for the Japanese side.

When Perry returned to the United States in 1855, Congress voted to grant him a reward of $20,000 (US $549,000 in 2020) in appreciation of his work in Japan. He used part of this money to prepare and publish a report on the expedition in three volumes, titled Narrative of the Expedition of an American Squadron to the China Seas and Japan. He was also promoted to the grade of rear-admiral on the retired list (when his health began to fail) as a reward for his service in the Far East.

Perry spent his last years preparing for the publication of his account of the Japan expedition, announcing its completion on December 28, 1857. Two days later he was detached from his last post, an assignment to the Naval Efficiency Board. He died awaiting further orders on March 4, 1858, in New York City, of rheumatic fever that had spread to the heart, compounded by complications of gout and alcoholism.

Initially interred in a vault on the grounds of St. Mark’s Church in-the-Bowery, in New York City, Perry’s remains were moved to the Island Cemetery in Newport, Rhode Island on March 21, 1866, along with those of his daughter, Anna, who died in 1839.

In 1873, an elaborate monument was placed by Perry’s widow over his grave in Newport.