Established 28 December 1941 as the Marine Corps Depot of Supplies, MCLB Barstow was transferred from the US Navy to the Marine Corps to supply and equip Fleet Marines. Barstow was selected as a logistics base, well away from the sea, because it is a transportation hub with dry conditions, good for storage and for rapidly shipping materiel.

The base conversion was rapid, the US then being at war, and the base expanded through the conflict. By the end of the war the base had overexpanded its grounds, and additional land was acquired, additional housing, warehousing, and recreation facilities. In 1956 the Commanding General, Depot of Supplies, transferred his flag from San Francisco, increasing the prestige of Barstow. In the 1960s and 1970s the base increased its support activity, and in 1978 changed it's name to the present one.

MCLB Barstow has the distinction of hosting the only mounted color guard of the Marine Corps, riding gold palomino horses with red trappings and dress blue riders.