From the partitioning of the Ottoman Empire in 1922 until 1944, had been under the control of France as a part of the League of Nations Mandate for Syria and the Lebanon.

The United States appointed George Wadsworth as agent and consul general to Syria and Lebanon on October 9, 1942, to provide a quasi-diplomatic presence in Damascus until the United States determined that Syria achieved effective independence in 1944.

The United States established diplomatic relations with Syria when George Wadsworth presented his credentials as Envoy Extraordinary and Minister Plenipotentiary on November 17, 1944.

Interests Section in Syria was established on February 8, 1974, in the Italian Embassy with Thomas J. Scotes as Principal Officer.

A series of chargés d’affaires represented the U.S. until the appointment of Robert Stephen Ford in January 2011.