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.

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.

On 13 February 1932 she departed the Caribbean to begin 13 months of plane guard duty and torpedo practice along the California coast.

She returned to Guantanamo Bay Naval Base, Cuba on 1 May 1933 for general drill and battle problem exercises, and on 26 May she sailed for Norfolk, Virginia to undergo self-upkeep on rotating reserve.

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.

After attending the Presidential Regatta in September, Jacob Jones prepared to sail for Europe to join Squadron 40-T in the Mediterranean Sea.

Resuming her coastal operations, Jacob Jones conducted plane screening patrols from Norfolk to Newport, Rhode Island and in December she escorted the submarine Seadragon during its Caribbean shakedown.

Organized in September 1939 as a response to the war in Europe, the Neutrality Patrol was ordered to track and report the movements of any warlike operations of belligerents in the waters of the Western Hemisphere.

In September, Jacob Jones departed Norfolk for New London, Connecticut, where her crew underwent intensive ASW sound school training.

Jones received two months of upkeep and inspection at Norfolk and on 1 December 1941, departed for convoy escort training along the New England coast.

While steaming to join Convoy SC 63, bound for the British Isles, the destroyer made an underwater contact and commenced a depth charge attack.

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.

On the morning of 27 February 1942, Jacob Jones departed New York harbor and steamed southward along the New Jersey coast to patrol and search the area between Barnegat Light and Five Fathom Bank.

At 1530 she spotted the burning wreckage of tanker R. P. Resor, torpedoed the previous day east of Barnegat Light; Jacob Jones circled the ship for two hours searching for survivors before resuming her southward course.

As she stopped dead in the water, unable to signal a distress message, a second torpedo struck about 40 feet (12 m) 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.

Oily decks, fouled lines and rigging, and the clutter of the ship's strewn twisted wreckage hampered their efforts to launch the boats.

By 1100, 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.