Pope was initially placed in reduced commission at Philadelphia and assigned to Squadron 3, Division 39 of the Atlantic Reserve Fleet. During 1921 she alternated between her winter base at Charleston and her summer one at Newport and escorted President Harding to Plymouth Mass. 30 July–1 August. She engaged in maneuvers with the battleship divisions off Guantánamo Bay from 12 January until her return to Philadelphia 27 April.

After a refit, Pope departed 12 May for duty in the Pacific. She passed through the Straits of Gibraltar 3 July and transited the Suez Canal 15–25 July. Pope joined Squadron 15 Division 43 of the Asiatic Fleet at Chefoo, China 26 August and participated in fleet exercises off Chefoo until her departure 28 October for her winter base at Cavite, Philippines.

In the Orient Pope protected American lives and interests during the civil strife in China. She first served with the Yangtze Patrol Force 9 September–9 October 1923 and continued to make her presence known through repeated patrols until 1931.

Notable exceptions were duty off Japan in connection with the Army “Round the World Flights” in 1924, a visit to French Indo-China in 1926 and a visit to Japan in 1929. From 1931 until 1937 Pope continued to “show the flag” off the China coast during the summers and spent the winters in the Philippines engaging in division maneuvers. She was reassigned to Squadron 5, Division 15 on 3 February 1933. Pope made visits to French Indo-China in 1935 and in 1938, two visits to Japan in 1934 and 1935 and one to the Netherlands East Indies in 1936.

Increased tension on China’s northern borders due to the Japanese invasion of Manchuria made it necessary for Pope to evacuate Americans from northern Chinese ports such as Lao Yao and Tsingtao to Shanghai beginning 19 September 1937. From 15 July to 20 September 1938 she cruised in Chinese waters off Chinwangtao and returned 5 June 1939 with the South China Patrol Force removing American consulates and nationals. Pope was stationed off Swatow and Pehtaiho 14 June–19 August observing the Japanese Fleet en route to Swatow and the subsequent bombing and occupation of the city. She remained in this area until her return to Manila 12 October for neutrality patrol off the Philippines. Pope was transferred to Division 59 of the Asiatic Fleet 6 May 1940 and resumed patrolling off China 11 May–24 June. Pope returned to Manila in late June on neutrality duty and remained on station there until 11 December 1941 when she got underway for Balikpapan.

Pope had a distinguished record in the Netherlands East Indies in the early days of World War II. During the Battle of Makassar Strait, she made close-quarter torpedo and gun attacks which helped delay Japanese landings at Balikpapan. Llater, in the Battle of Badoeng Straits, she impeded the invasion of Bali.

In the Battle of the Java Sea, Pope and HMS Encounter were directed to escort HMS Exeter away from the action. On the evening of 28 February 1942 the heavy cruiser and two destroyers left Soerabaja and proceeded north. Midway between Java and Borneo enemy surface and air forces launched an attack the next morning. The three Allied ships fought four Japanese heavy cruisers and four destroyers throughout a fierce three-hour action and succeeded in damaging a number of enemy ships. Pope fired all torpedoes and 140 salvos of ammunition.

Shortly before noon 1 March the two British ships were destroyed by gunfire, and an hour later Pope was attacked and sunk by 12 dive-bombers after sustaining many direct hits. She was struck from the Navy List 8 May 1942.

Pope received two battle stars and the Presidential Unit Citation for her World War II service.