A history of strained and suspended relations throughout the Cold War led to the embassy being forced to close at various times, including permanently between 1965 and 1969 and again between 1975 and 1991.

The United States established its first direct diplomatic relationship with Cambodia on June 29, 1950, with the appointment of Donald R. Heath as Envoy Extraordinary and Minister Plenipotentiary.

Operations were initially conducted from the renowned Hotel Le Royal until a Legation office and US Information Service library were established in a new location.

[1] A new embassy designed by Eliot Noyes in 1960 was proposed, but became one of various projects shelved by congressman Wayne Hays over disputes about the style and necessity of new US diplomatic architecture.

Ambassador Herbert D. Spivack suspected that Prince Sihanouk had purposely orchestrated the incident and a similar event at the British embassy.

The second incident in 1965 led to less destruction, with the embassy not being breached, but rocks were thrown through the windows and there were still thousands of dollars of damages incurred.

[6] With the further penetration of Vietnamese communist forces into Cambodia, Sihanouk was anxious to restore relations, and the US Embassy reopened on August 16, 1969.

[24] The new complex was officially opened on January 18, 2006, in a ceremony initiated by diplomat Christopher R. Hill, then Assistant Secretary of State.

As a "gift", prime minister Hun Sen, who had talked to Hill earlier that day, released four political prisoners: Rong Chhun, Kem Sokha, Mam Sonando as well as activist and Cambodian Center for Human Rights member Pa Nguon Tieng.