The second Meredith (DD-434) was laid down 1 June 1939 by Boston Naval Shipyard; launched 24 April 1940; sponsored by Miss Ethel Dixon Meredith, and commissioned 1 March 1941, Lt. Comdr. William F. Mendenhall, Jr., in command.

Following shakedown in Cuban waters, Meredith returned to Boston 8 June 1941 and was assigned to Destroyer Division 22. Departing Boston 6 July, she engaged in patrol duty, exercises, and flight operations along the southern coast until 20 September. From 28 September until 31 January 1942, Meredith was based at Halfjordur, Iceland, whence she patrolled between Iceland and the Denmark Straits. On 17 October 1941, she rescued survivors of torpedoed British steamer Empire Wave.

Following the attack on Pearl Harbor, Meredith engaged in escort and antisubmarine patrol between Iceland and the Denmark Straits, until she departed Halfjordur late in January escorting a convoy to Boston. She sailed from Boston for Norfolk 18 February 1942 screening Washington (BB-56), and there joined Hornet (CV-8) in TF 18.

The force left Norfolk 4 March on a mission as secret as it was important, passed through the Panama Canal, and reached San Diego 21 March. Departing San Francisco 2 April, the force rendezvoused with TF 16, 13 April and sailed for the famous "Shangri-La" raid on Tokyo. On 18 April, the Army bombers were launched for this first carrier-based attack on Japan, and Meredith made course for Hawaii, arriving 25 April.

Between 13 May and 21 June Meredith escorted fleet oilers bound for New Caledonia, patrolled off Bulari Passage and escorted carrier Tangier (AV-8), returning to Pearl Harbor. Following gunnery and tactical practice, Meredith departed Pearl Harbor, Harbor 15 August 1942 for Samoa, arriving Pago Pago 30 August. Meredith next escorted Transport Force 2 to the Solmons with reinforcements landed on Guadalcanal 20 September, then sail for patrol duty in the New Hebrides.

Departing Espiritu Santo 12 October to escort a convoy of freighters to Guadalcanal, Meredith engaged Japanese aircraft on the morning of 15 October, then shortly after midday was attacked by a force of 35 bombers and torpedo planes from enemy carrier Zuikaku. Meredith fought fiercely against these terrible odds, and brought down three of her attackers before she sank. Only seven officers and 56 men survived the attack and the three ensuing days of exposure to the open sea and sharks until they were rescued by destroyer Grayson (DD-435) and fleet tug Seminole (AT- 65).