Moffett was on USS Charleston (C-2) when she sailed across the Pacific and captured Guam. Ultimately ending up in the Philippines, a month after the US victory at Manila Bay, the Charleston then shelled enemy positions in support of American and Filipino troops at the Battle of Manila (1898).

Commander Moffett was the captain of the Chester during the Tampico Affair. In December 1915 Moffett received the Medal of Honor for his captaincy of the USS Chester in a daring and dangerous night landing in 1914 at Veracruz, Mexico.

In World War I, he was commander of the Great Lakes Naval Training Center near Chicago, where he established an aviator training program. While commanding the battleship USS Mississippi (1918–1921) he supported the creation of a scout plane unit on the ship.

Although not himself a flyer, Moffett became known as the "Air Admiral" for his leadership of the Navy's Bureau of Aeronautics from its creation in 1921 with Captain Henry C. Mustin as its first Assistant Chief. In this role, he oversaw the development of tactics for naval aircraft, the introduction of the aircraft carrier, and relations with the civilian aircraft industry. A master politician, he maintained official support for naval aviation against Billy Mitchell, who favored putting all military aircraft into a separate air force. In that regard, Moffett benefited from his longstanding friendship with Franklin D. Roosevelt, who had been appointed Assistant Secretary of the Navy by Woodrow Wilson in 1913.

Moffett was a strong advocate of the development of lighter-than-air craft, and lost his life when the USS Akron, then the largest dirigible in the world, crashed in the Atlantic Ocean during a storm off the coast of New Jersey on April 4, 1933.