During the Vietnam War, between 1962 and 1971, the United States military sprayed nearly 20,000,000 U.S. gallons (76,000 m3) of various chemicals – the "rainbow herbicides" and defoliants – in Vietnam, eastern Laos, and parts of Cambodia as part of Operation Ranch Hand, reaching its peak from 1967 to 1969. As the British did in Malaya, the goal of the U.S. was to defoliate rural/forested land, depriving guerrillas of food and concealment and clearing sensitive areas such as around base perimeters and possible ambush sites along roads and canals. Samuel P. Huntington argued that the program was also a part of a policy of forced draft urbanization, which aimed to destroy the ability of peasants to support themselves in the countryside, forcing them to flee to the U.S.-dominated cities, depriving the guerrillas of their rural support base. 

Agent Orange was usually sprayed from helicopters or from low-flying C-123 Provider aircraft, fitted with sprayers and "MC-1 Hourglass" pump systems and 1,000 U.S. gallons (3,800 L) chemical tanks. Spray runs were also conducted from trucks, boats, and backpack sprayers. Altogether, over 80 million litres of Agent Orange were applied.

The first batch of herbicides was unloaded at Tan Son Nhut Air Base in South Vietnam, on January 9, 1962. U.S. Air Force records show at least 6,542 spraying missions took place over the course of Operation Ranch Hand. By 1971, 12 percent of the total area of South Vietnam had been sprayed with defoliating chemicals, at an average concentration of 13 times the recommended U.S. Department of Agriculture application rate for domestic use. In South Vietnam alone, an estimated 39,000 square miles (10,000,000 ha) of agricultural land was ultimately destroyed.