At the Battle of the Coral Sea, the day before the major engagement Monaghan carried messages, keeping this way the radio silence, and missing out on the thick of the battle. With the loss of the Lexington, she was attached to the screen of the Enterprise. In the Battle of Midway she was ordered to save a downed pilot, when she came across the badly damaged Yorktown, and joined other escorts to prevent the Japanese to inflict further damage to the ship. However, one of Japan's most skilled sub-skippers, Cmdr Tanaka manages to sinks the Yorktown and the destroyer Hammann.

After the battle she was sent North, to the Aleutians, where in bad weather she collided with another vessel, forcing her into the repair dock. On 17 November, near the Fijis she suffered damage again, bending her propellers in shallow waters. After repairs she was sent again to the Aleutians, participating in the battle off Komandorski Islands. She spent the summer cruising around the Aleutians. On 20 June, she fought an unidentified foe, without seeing it, directing her fire solely based on information from the radar. 2 days later she pursued and attacked a submarine, which ran aground in the shallow waters, and was abandoned. She was identified as the I-7. After she escorted convoys, then she was attached to three escort carriers, and took part in the invasion of Tarawa. The following months she fulfilled convoy escort duties, as well as screening task forces, engaged in landings like Kwajalein, Truk and Saipan.

USS Monaghan sinks during a typhoon on the 18 Dec, with two other destroyers, east of Samar, Philippines in position 14º57'N, 127º58'E. Only six of her crew were ever found by the destroyer USS Brown. 257 crew died including the Commanding officer Lt Cmdr Floyd Bruce Garrett these six survivors were transferred to the hospital ship USS Solace on Christmas eve. They had been in the water for 4 days. All were treated for Shock, Exposure and dehydration otherwise in fair shape considering their experience.

Before her loss, USS Monaghan received 12 Battle Stars for her services.