After drydocking and repairs during the fall of 1941, O'Brien left Norfolk, Virginia on 15 January 1942 along with the battleship Idaho and the destroyer Mustin, and then steamed for the Pacific Ocean.

O'Brien steamed with a convoy for the Western Pacific on 4 February 1942, but she was forced to return when a collision with the destroyer Case damaged her port side.

After operating out of Pearl Harbor and patrolling the Hawaiian atoll, French Frigate Shoals, O'Brien called at Midway Island in the latter part of March, escorting the seaplane tender Curtiss there to evacuate civilians.

After an increase and improvement of her antiaircraft batteries, she embarked passengers for transportation to the Naval Air Station at Palmyra Atoll, and then steamed out on 18 April with the destroyers Flusser and Mugford.

On 26 May, she supported the occupation of Wallis Island, previously taken over by the Free French, and then she joined the auxiliary vessel Procyon on 19 June for the return voyage to Pearl Harbor.

While escorting a convoy of troop transports en route to Guadalcanal, the combined Task Forces 17 and 18 were attacked by the Japanese submarine I-19 on 15 September 1942.

The aircraft carrier Wasp was sunk, and the battleship North Carolina and O’Brien were damaged by a spread of six torpedoes from the submarine.