Assigned to the Atlantic Fleet Benham patrolled off Newfoundland during most of 1939 and then shifted to the Gulf of Mexico. Ordered to the Pacific, she arrived at Pearl Harbor 14 April 1940. After alternating between Californian and Hawaiian waters, the destroyer served as an escort for Enterprise (CV-6) during the delivery of Marine planes to Midway (28 November–8 December 1941), thus missing the attack on Pearl Harbor. Benham served with the Enterprise and Saratoga (CV-3) task forces off Hawaii and with TF 16 during the Doolittle raid on Tokyo (B-25 April 1942). She continued operating with TF 16 through the Battle of Midway (3–6 June), during which she rescued 720 survivors from Yorktown (CV-5) and 188 from Hammann (DD-412), landings on Guadalcanal and Tulagi (7–9 August), and the Battle of the Eastern Solomons (23–25 August). Benham joined TF 64 on 15 October as part of the naval covering force off Guadalcanal. During 14–15 November she took part in the Naval Battle of Guadalcanal. At 0038, 15 November she took a torpedo forward, lost her bow, and had to withdraw from the battle. Benham doggedly stayed afloat, making slow headway towards Guadalcanal during the 15th but, by 1637, further progress was impossible and her valiant crew had to abandon. Gwin (DD-433) picked up the survivors and sank the hulk at 1938 by shellfire.
Benham (DD-397) received five battle stars for her 11 months service in World War II.