Following the Japanese attack on Pearl Harbor in December 1941, she and her squadron were transferred to the Pacific. Early in 1942, as a unit of Task Force 17, Sims operated in the Central and Southern Pacific escorting Yorktown (CV 5). In early May, she was assigned to escort oiler Neosho (AO 23) as Yorktown and Lexington (CV 2) maneuvered to confront a Japanese force advancing to attack Port Moresby, New Guinea.
In the early phases of the resulting Battle of the Coral Sea on 7 May, enemy carrier aircraft found the destroyer and oiler. An overwhelming air attack sank Sims and damaged Neosho so badly that she was scuttled.