After returning to Pearl Harbor they sortied 30 April to aid Yorktown (CV-5) and Lexington (CV-2) in the Battle of the Coral Sea, but reached the scene after the battle was over. TF16 returned to Pearl Harbor and departed again, this time for the Battle of Midway. After Midway the force remained at Pearl Harbor for a month before departing for the Solomon Isles by way of the Tonga Islands. On the 7th and 8th of August, Monssen with Buchanan (DD-484) stood off Gavutu and Tanambago, circling those islands and providing fire support to units of the 2d Marine Regiment. She was then assigned to the screening forces guarding the eastern approaches to Sealark, Lengo, and Nggela Channels.

Monssen was one of the ships designated to escort Saratoga (CV-3)  to the Tonga Islands after she was damaged in the Battle of the Eastern Solomons She then took up duties patrolling the sea routes to Guadalcanal.

Monssen returned to Guadalcanal 18 September to insure the integrity of an Allied supply line and to block Japanese efforts at resupply. On 8 November, she departed Noumea with two cruisers and two other destroyers as TG 67.4, under Rear Admiral Callaghan, as escort for transports carrying reinforcements to the marines on Guadalcanal. At the same time, another convoy set out from Espiritu Santo, covered by one cruiser and four destroyers under Rear Admiral Scott. Arriving off Lunga Point on the 12th, a day after those from Espiritu Santo they commenced unloading. 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 transports were pulled out, escorted through Lengo Channel, and seen safely on their way to Espiritu Santo. Then Admiral Callaghans force, heavily outnumbered even with the addition of, Admiral Scott's ships reversed course and steamed back to engage the enemy in the initial action of what would later be called the Naval Battle for Guadalcanal.

Shortly, after 0140, 13 November, they sighted the enemy fleet, under Vice Admiral Abe, 3 miles north of Kukum. 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.

Battle was given at 0150. At about 0220 Monssen forced to rely on radio information and optics, was spot lighted, hit by some 37 shells, and reduced to a burning hulk. Twenty minutes later, completely immobilized in all departments, the ship was ordered abandoned. After daybreak Monssen was still a floating incinerator. C. C. Storey, BM2c, L. F. Sturgeon, GM2c, and J. G. Hughes F1c, climbed back into the inferno and rescued eight men still aboard and alive, five of whom lived after reaching land. The survivors, 40 percent of the crew, were picked up at about 0800 and taken to Guadalcanal. The ship itself continued to blaze until early afternoon, when the waters of Ironbottom Sound closed over her.

Monssen was awarded four battle stars for World War II service.