After shakedown training out of the Virginia Capes, Gamble sailed from New York 13 January 1919 to take part in maneuvers off Cuba; Key West, Fla.; and the New England seaboard until June 1919. Following overhaul at Norfolk, she joined the Pacific Fleet at San Diego 7 August 1919 and operated along the Pacific coast until placed in reserve status in the Mare Island Navy Yard 1 December 1919. In October 1920, she came out of reserve and assisted the flotilla in torpedo practice; maneuvered with the Battle Force; and cruised along the California coast as a training ship for reservists. She decommissioned at San Diego 17 June 1922.

Gamble recommissioned 24 May 1930; was reclassified (DM-15) on 13 June, and converted into a light minelayer in the Mare Island Navy Yard. Arriving Pearl Harbor from the West Coast, she became flagship of Mine Squadron 2 in July 1930 and later served as flagship of Mine Division 1, Mine Squadron 1. She cruised Hawaiian waters instructing Naval Reservists in mine warfare and acted as plane guard and radio tracker for seaplanes, each year participating in fleet readiness and fleet problems until she returned to San Diego where she decommissioned 22 December 1937. Recommissioning 25 September 1939 as Europe was plunged into World War II, she joined Mine Division 5 in patrol and schoolship duties out of San Francisco. In April 1941 she proceeded to Pearl Harbor for war readiness patrol in Hawaiian waters as a unit of Mine Division 2.

On 7 December 1941, Gamble had returned from offshore patrol, when her peaceful Sunday morning routine was broken by the first of the Japanese carrier-based planes which pounded American ships in the harbor. Gamble's gunners joined the fire of other warships and had the satisfaction of seeing one enemy plane fall into the water on her port beam. After the attack she took antisubmarine patrol station in the screen of the carrier Enterprise (CV-6), and later guarded the approaches to Pearl Harbor. In mid-February 1942 she headed south in the escort for a convoy to Pago Pago, Samoa; then joined Ramsay in laying a protective mine field off Tutuila. At the end of March the two minelayers shifted to the Fiji Islands, to lay a minefield in Nandi waters 7–14 April. Returning to Pearl Harbor for heavier armament, Gamble helped safeguard convoys to Midway during the time of that crucial and historic battle, then headed south with Breese and Tracy to lay a defensive mine field off the entrance to Second Channel, Espiritu Santo, New Hebrides Islands.

On 27 August 1942 Gamble joined a task unit headed to Guadalcanal. Although designated a destroyer-minelayer, the old four-piper still carried antisubmarine gear. On the morning of 29 August, when her lookouts spotted a large enemy submarine, she immediately went into action. After several depth charge attacks, Gamble ran through large oil slicks, found deck planking, and observed a large air bubble break the surface. Later her victim was identified as Japanese submarine I-123, whose dying radio had signaled "under heavy enemy attack." That afternoon she proceeded at full speed to Nura Island where she rescued four stranded aviators from aircraft carrier Saratoga. Continuing to aid in the bitter struggle for Guadalcanal, she transported 158 marines to the island 31 August, patrolled off Lunga Roads, then on 5 September assisted in freeing grounded transport William Ward Burrows (AP-6) and escorted her to Espiritu Santo, New Hebrides Islands. Her patrol, escort, and transport duty continued as the drive for Guadalcanal pressed on to victory.

Five minutes after midnight, 6 May 1943, Gamble, with minelayers Preble and Breese turned simultaneously in rain squalls which broke at times to disclose each to the other in perfect formation. Making 15 knots, each ship dropped a mine every 12 seconds, planting over 250 mines in 17 minutes across Blackett Strait, the western entrance to Kula Gulf and directly in the favorite route of the worrisome "Tokyo Express." The ships then sped north to join the protective screen of Rear Admiral Ainsworth's cruiser-destroyer force before refueling at Tulagi. On the night of 7-8 May, four Japanese destroyers entered the mined waters. One, Kurashio, went down, two others, Oyashio and Kagero, were badly damaged and sent out calls for help that brought the fourth destroyer Michishio to the scene. Aircraft, alerted by a coastwatcher, intercepted the rescue operation, sinking the two destroyers and sending Michishio limping back to port, badly damaged.

On 30 June 1943, during the invasion of New Georgia, Gamble laid a string of mines off the beachhead, before returning to Tulagi. In July welcome orders sent her back to the United States for overhaul. She headed west again 20 September 1943. Her minelaying duties then brought her to Empress Augusta Bay 1–2 November 1943 to support landing operations; Bougainville Strait, 7–8 November; Purvis Bay, Florida Island, 23–24 November, thence to the New Hebrides Islands for escort duty among the Solomons until she returned to San Francisco 12 October 1944.

After overhaul and refresher training, Gamble departed San Diego 7 January 1945, en route via Hawaii and the Marshalls to Iwo Jima where she arrived 17 February, to lend fire support to the various sweeping units, and to explode floating mines. During her shelling a direct hit on an ammunition dump exploded the enemy magazine like a giant firecracker at the foot of Mt. Surabachi.

On 18 February 1945 Gamble was hit just above the waterline by two 250-pound bombs. Both firerooms immediately flooded and she became dead in the water with two holes in her bottom as all hands fought raging fires, jettisoned topside weight and shored damaged bulkheads. Five men were killed, one missing in action, and eight wounded. As marines stormed the shores of Iwo Jima the next day, Gamble was taken in tow by Dorsey who turned her over to LSM-126 for passage to Saipan. She arrived at Saipan 24 February and went alongside Hamul for repair.

Some hope remained for Gamble for a long time, but on 1 June 1945 she decommissioned, and on 16 July she was towed outside Apra Harbor, Guam, and sunk.

Gamble received seven battle stars for service in World War II.