Following shakedown to Casco Bay, Maine, and escort duty off Halifax, Nova Scotia, Murphy joined the Center Attack Group, Western Naval Task Force, at Norfolk, Virginia, sailing in late October for Fedhala, Morocco, to participate in Operation Torch, the invasion of North Africa.

Murphy remained off Fedhala through the Naval Battle of Casablanca, driving off an air attack 9 November, until sailing for Boston to complete repairs, arriving on the 24th.

The destroyer next escorted convoys between New York and Panama, and Norfolk and Casablanca, until joining the "Dime" attack force screen for the Amphibious Battle of Gela, Sicily, in July 1943, "Operation Husky".

She remained there, giving fire support and conducting screen duty for the transports through mid-June, engaging in a gun duel with shore batteries 8 June, and repelling numerous German U-boat and torpedo attacks.

The destroyer resumed operations in late 1944, joining Quincy at Norfolk to escort that ship carrying President Franklin D. Roosevelt to the Malta and Great Bitter Lake, Egypt, Conferences.

[4] With her passengers disembarked, the warship then sailed for New York for a minor yard period, joined an antisubmarine "killer" group on duty off New England and Nova Scotia, and then in May escorted one of the last convoys to Oran, Algeria, and back.

On 2 June 1945, with war in the Atlantic won, Murphy entered the Boston Navy Yard for refit prior to assignment to the Pacific Fleet.

Being assigned to the 5th Fleet on occupation duty in southern Japanese waters, she visited Nagasaki, Yokosuka, Wakayama, and Nagoya until departing Okinawa 21 November for the United States.