In 1905, the Order of Saint Benedict (OSB) decided to establish a mission near the Drysdale River. The mission was established in 1908, 20 kilometres north-east of the present site, at Pago, near the southern end of Napier Broome Bay, by Benedictine monks from New Norcia. In 1937, water supply problems forced the missionaries to move to the present site at Kalumburu Pool, on the King Edward River.
Following the outbreak of World War II, the Australian government commissioned an airfield at the mission. After Japanese forces occupied the Dutch East Indies in 1942, Drysdale became a frontline Royal Australian Air Force (RAAF) base, acting as a staging post for Allied squadrons based further south. The airfield was a refuelling and ammunition depot for the RAAF anti-submarine aircraft operating between Darwin and Fremantle. On 19 February, the mission provided assistance to the crew and passengers of the merchant vessel Koolama, which had been attacked by Japanese planes.
In February 1943, Allied signals intelligence suggested that Japanese aircraft would be built up in Timor for attacks on Darwin. Eight Beaufighters from No. 31 Squadron RAAF were despatched to Drysdale River, to prepare for a pre-emptive strike. On 28 February, it was confirmed that the enemy aircraft had arrived at Penfui, near Kupang. An early morning strike destroyed 12 Japanese aircraft on the ground and damaged another 10. Two Beaufighters were damaged by Japanese fighter aircraft but returned to Drysdale River.
On 27 September 1943, the base and settlement were attacked by 21 Japanese Kawasaki Ki-48 bombers, based at Kupang, Timor, with a fighter escort. The Superior of the mission, Father Thomas Gil O.S.B, aged 45 years.and five Aboriginals ranging from the age of 1 year to 45 years were killed. This included a mother and son. All victims were buried together on mission grounds, the Aboriginals on either side of Father Thomas, following the funeral at the damaged church. Many buildings at the mission were also destroyed or severely damaged during the raid.