VMO-251 was activated on December 1, 1941. While not the Marines first observation squadron, it was the first to be equipped with a plane specific for its mission. It would not be until early 1942 that the squadron received its modified Grumman F4F Wildcats (F4F-3P). The planes retained their four machine guns while modified to carry cameras. VMO-251 was slated to fight out of Guadalcanal, but a last minute change had it going to Espiritu Santo in the New Hebrides. They arrived there in early August 1942, after a short stay in New Caledonia. While at Espiritu Santo, the squadron supplied pilots and ground crew to the Cactus Air Force. The pilots fought in numerous engagements during the Guadalcanal campaign. VMO-251 finally made it to Guadalcanal in January 1943 and left in May 1943. The squadron was reconstituted in the US, and received the Chance F4U Corsair. By the summer of 1944 the squadron was back in the South Pacific, flying many missions out of Piva North Airfield, Bougainville, in conjunction with the reduction and isolation of the Japanese strongholds on Bougainville, New Britain and New Ireland. In January 1945, the squadron was flying out Guiuan Airfield, Samar, Philippine Islands. It was also re-designated as VMF-251. The squadron was deactivated in June 1945. Its planes and personnel were transferred to other squadrons or sent back to the states.