In 1940 she was reassigned to the Hawaiian islands. When the Japanese attacked Pearl Harbor on December 7th, 1941, she left port with a mixed crew from different ships in search for the attacking fleet, finding no enemy. She spent the next few weeks patrolling around Oahu, and then joined the destroyer screen around the Lexington. She was soon reassigned for escort duties, and on January 30th, 1942 she was attacking a Japanese submarine on the way back to Hawaii from the Canton Island. She remained in this role until the invasion of the Solomon Islands begun, when she was attached to TG 62.6, the screening group for the transports bound to Guadalcanal. After the battle off Savo Island she had the sad duty to scuttle the badly damaged cruiser HMAS Canberra. Later in the year she patrolled the waters around Australia.

In May 1943, Selfridge was reassigned to the 3rd Fleet. On the 6th October, Selfridge, along with USS O'Bannon and Chevalier intercepted a Japanese force of 6 destroyers and 4 other ships. They went into attack, but the results were disastrous. Chevalier was sunk, O'Bannon and Selfridge suffered extensive damage. Selfridge crew suffered a casualty of 13 killed, 11 wounded and 36 missing. After repairs and training with the new crew, she returned to action in May 1944, participating in the battles around Guam and Saipan. In September 1944 she sailed to New York for a major refit and overhaul, then she joined TF65 and serving as flagship she escorted convoys in the Atlantic until the end of the war.

She was  stricken on 1 November 1945 and sold for scrap on 20 December 1946, she was eventually scrapped in October 1947. USS Selfridge received 4 Battle Stars for her services during WW2.