Her escort and patrol duties changed from neutral to belligerent 7 December 1941, continuing until 9 February 1942 when she entered the Boston Navy Yard for overhaul in preparation for her transfer to the Pacific Fleet.

In the early morning hours of 18 April the force was sighted by the enemy and the air raid was launched to bomb their targets of Tokyo, Nagoya, Osaka, and Kobe.

Following the Doolittle Raid, the force returned to Pearl Harbor, from which it sortied 30 April to aid the carriersYorktown and Lexington in the Battle of the Coral Sea.

On 7–8 August, Monssen with Buchanan stood off Gavutu and Tanambogo, circling those islands and providing fire support to units of the 2nd Marine Regiment as the U.S. Navy struck with the first of its giant amphibious assaults.

On 8 November, she departed Nouméa with two cruisers and two other destroyers as Task Group 67.4 (TG 67.4), under Rear Admiral Daniel J. Callaghan, as escort for transports carrying reinforcements to the Marines on Guadalcanal.

By dusk as reports of Japanese ship movements from Truk increased, 90 percent of the transports had been unladen despite afternoon torpedo plane attacks, one of which had cost Monssen the use of her fire control radar.

The enemy was headed toward Henderson Field — to bombard it and cripple Allied air operations long enough to sneak in 11 of their transports, then en route to relieve their beleaguered comrades fighting on the island.

Monssen, forced to rely on radio information and optics, was spotlighted, hit by some 39 shells, including three of battleship caliber, and reduced to a burning hulk.

In 1992, an expedition headed by oceanographer Robert Ballard found the wreck of Monssen and other ships sunk during the Solomon Islands battles.