Jacob Jones was decommissioned on 24 June 1922 and placed in reserve until recommissioned on 1 May 1930, and was assigned to Neutrality Patrol duties out of Charleston, South Carolina on 4 April 1940.
Recommissioned 1 May 1930, Jacob Jones trained in coastal waters from Alaska to Mexico as a plane guard for the Navy's budding aircraft carriers. Following Battle Fleet maneuvers during August, she entered Mare Island in November for repairs. The destroyer sailed 4 February 1931 for Panama, where she resumed plane guard duty for . Jacob Jones transited the Panama Canal 22 March and sailed for maneuvers in the Caribbean. She sailed for the United States 1 May and took part in joint Army-Navy maneuvers in the Chesapeake Bay 26 to 29 May. During the remainder of the summer, she operated with Destroyer Division 7 along the New England coast before retiring to the Boston Navy Yard 2 October for overhaul.
Jacob Jones steamed from Boston 1 December for maneuvers off Haiti. On 13 February 1932 she departed the Caribbean to begin 13 months of plane guard duty and torpedo practice along California. She returned to Guantánamo Bay, Cuba, 1 May 1933 for general drill and battle problem exercises, and on the 26th she sailed for Norfolk to undergo self-upkeep on rotating reserve.
Following 2 months of overhaul at Charleston, Jacob Jones returned to Guantanamo 29 November for scouting and firing exercises. She interrupted her maneuvers 29 June 1934 and sailed for Port-au-Prince, Haiti, where she served as an escort during President Franklin D. Roosevelt's "Good Neighbor" visit to Haiti. She resumed Caribbean operations in July and participated in landing force exercises at Guantanamo Bay during September. She retired from the Caribbean late in November and entered Norfolk Navy Yard 3 December 1934 for several months of upkeep.
In May 1935 Jacob Jones embarked midshipmen from the Naval Academy for an Atlantic training cruise. She returned to Norfolk 7 June for 3 months of coastal patrols and maneuvers. She steamed to New York in September to participate in destroyer maneuvers and operated out of New York until entering Brooklyn Navy Yard January 1936 for upkeep and inspection.
On 15 June 1936, Jacob Jones departed New York with reserve officers on board for training cruises in the Caribbean which continued through September. In October she participated in joint Army-Navy coastal maneuvers; and, following her annual inspection at Norfolk, she participated in minesweeping training during February 1937. In March she trained officers of the 5th Fleet Reserve and in June she resumed training cruises for midshipmen. She continued to operate as a practice ship for reserve officers until 15 January 1938 when she departed Norfolk for fleet landing exercises and battle maneuvers in waters off Puerto Rico and the Virgin Islands. Jacob Jones returned to Norfolk 13 March for overhaul. In June she resumed operations out of Norfolk, serving as a carrier plane guard and conducting torpedo and gunnery practice.
After attending the Presidential Regatta in September, Jacob Jones prepared to sail for Europe to join Squadron 40-T in the Mediterranean. Organized in September 1936 to protect and evacuate Americans from Spain during the civil war, the squadron remained in the western Mediterranean. Departing Norfolk 26 October, Jacob Jones reached Gibraltar 6 November, and arrived Villefranche 17 November. She operated out of that French Mediterranean port on patrol until 20 March 1939. She visited Algiers 24 to 25 March 1939 and, during the next 7 months, steamed to various Atlantic European ports from Rotterdam to Lisbon. Departing Lisbon 4 October, she sailed for the United States and anchored at Norfolk the 14th.
Resuming her coastal operations, Jacob Jones conducted plane screening patrols from Norfolk to Newport, and in December she escorted during the new submarine's Caribbean shakedown.
In September, Jacob Jones departed Norfolk for New London, Connecticut, where her crew underwent intensive ASW sound school training. Returning briefly to Norfolk 6 December, she sailed to Key West for further ASW training. She resumed her operations with the Neutrality Patrol in March 1941, patrolling the waters from Key West to Yucatan Channel. In May she joined the ships which guarded the waters of Vichy-controlled islands, Martinique and Guadeloupe in the Lesser Antilles. Jacob Jones maintained her Caribbean operations throughout the summer.
On 30 September 1941 she departed Guantanamo with Destroyer Division 54 to prepare for escort duty in the North Atlantic. Jacob Jones received 2 months of upkeep and inspection at Norfolk and on 1 December 1941 departed for convoy escort training along the New England coast. Clearing Boston Harbor 12 December, she sailed to NS Argentia, Newfoundland, to begin her escort duty. On 16 December she escorted and through heavy seas to Boston and returned to Argentia the 24th. Jacob Jones once again departed Argentia 4 January 1942 escorting and . While steaming to join Convoy SC-63, bound for the British Isles, Jacob Jones made an underwater contact and commenced a depth charge attack. Losing contact with the submarine, she escorted her ships to the convoy and returned to Argentia 5 January.
Sailing from Argentia 14 January 1942, Jacob Jones joined Convoy HX-169, which was headed for Iceland. The convoy encountered a violent storm; heavy seas and winds of force 9 scattered its ships' convoy. Separated from the convoy, Jacob Jones steamed independently for Hvalfjörður, Iceland. Though hampered by a shortage of fuel, an inoperable gyro compass, an erratic magnetic compass, and the continuous pounding of the storm, Jacob Jones arrived on the 19th. Five days later, she escorted three merchant ships to Argentia. Once again heavy seas and fierce winds separated the ships; and Jacob Jones continued toward Argentia with one Norwegian merchantman. She detected and attacked another submarine 2 February 1942, but her depth charges yielded no visible results.
Arriving Argentia the 3d, she departed the following day and rejoined Convoy ON-59, bound for Boston. Reaching Boston 8 February, Jacob Jones received a week of repairs. She sailed on the 15th for Norfolk and 3 days later steamed from Norfolk to New York.
In an effort to stem the losses to Allied merchant shipping along the Atlantic coast, Vice Admiral Adolphus Andrews, Commander of the Eastern Sea Frontier, established a roving ASW patrol. Jacob Jones, Lt. Comdr. Hugh Black in command, departed New York 22 February for this duty. While passing the swept channel off Ambrose Light Ship, Jacob Jones made a possible submarine contact and attacked immediately. For 5 hours Jacob Jones ran 12 attack patterns, dropping some 57 depth charges. Oil slicks appeared during the last six attacks but no other debris was detected. Having expended all her charges, Jacob Jones returned to New York to rearm. Subsequent investigation failed to reveal any conclusive evidence of a sunken submarine.
At the first light of dawn 28 February 1942, undetected fired a spread of torpedoes at the unsuspecting destroyer. The deadly "fish" sped unsighted and two "or possibly three" struck the destroyer's port side in rapid succession.
According to her survivors, the first torpedo struck just aft of the bridge and caused almost unbelievable damage. Apparently, it exploded the ship's magazine; the resulting blast sheered off everything forward of the point of impact, destroying completely the bridge, the chart room, and the officers' and petty officers' quarters. As she stopped dead in the water, unable to signal a distress message, a second torpedo struck about 40 feet forward of the fantail and carried away the after part of the ship above the keel plates and shafts and destroyed the after crew's quarters. Only the midships section was left intact.
All but 25 or 30 officers and men, including Lt. Comdr. Black, were killed by the explosions. The survivors, including a badly wounded, "practically incoherent" signal officer, went for the lifeboats. Oily decks, fouled lines and rigging, and the clutter of the ship's strewn twisted wreckage hampered their efforts to launch the boats. Jacob Jones remained afloat for about 45 minutes, allowing her survivors to clear the stricken ship in four or five rafts. Within an hour of the initial explosion Jacob Jones plunged bow first into the cold Atlantic; as her shattered stern disappeared, her depth charges exploded, killing several survivors on a nearby raft. (As had happened to the in 1917).
At 08:10 an Army observation plane sighted the life rafts and reported their position to Eagle 56 of the Inshore Patrol. By 11:00, when strong winds and rising seas forced her to abandon her search, she had rescued 12 survivors, one of whom died en route to Cape May. The search for the other survivors of Jacob Jones continued by plane and ship for the next 2 days; but none were ever found.