In December 1941, soon after the US entered World War II, Walke went to the Pacific to join in the fight against Japan. She accompanied the aircraft carrier Yorktown (CV 5) during some of her early combat actions in the central and south Pacific. During the Battle of Coral Sea in early May, she operated with the Support Group of cruisers and destroyers that endured attacks by both Japanese and US land-based bombers, fortunately without significant damage to the ships.
Following an overhaul, Walke returned to the south Pacific in September 1942 to support the ongoing Guadalcanal Campaign. After two months of escort duties, she was attached to Rear Admiral Willis A. Lee’s battleship task force and sent on a mission to stop the Japanese from bombarding the US airfield on Guadalcanal. In the resulting second major surface action of the Naval Battle of Guadalcanal, on 15 November 1942, Walke was sunk by Japanese torpedoes and gunfire, with the loss of more than a third of her crew.