The United States recognized Luxembourg on May 31, 1878, when President Rutherford B. Hayes issued exequatur to François Berger, Consul General ad interim of Luxembourg at New York City.

On July 17, 1903, U.S. Ambassador to the Netherlands Stanford Newel presented his credentials as Envoy Extraordinary and Minister Plenipotentiary to Luxembourg. He remained resident at the The Hague.

On October 23, 1923, U.S. Ambassador to Belgium Henry P. Fletcher presented his credentials as Envoy Extraordinary and Minister Plenipotentiary to Luxembourg; he remained resident at Brussels.

Germany occupied Luxembourg on May 10, 1940, and the American Legation closed on July 15, 1940.

U.S. Ambassador to Canada Jay Pierrepont Moffat was accredited to the Government of Luxembourg in Canada; he remained resident at Ottawa.

The Government of Luxembourg moved to the United Kingdom on October 14, 1943. Anthony J. Drexel Biddle Jr. presented his credentials to the Government of Luxembourg in London on November 12th but he departed London shortly thereafter. Although Rudolph E. Schoenfeld was appointed Chargé d’Affaires on March 21, 1944, he did not present his credentials before his appointment was superseded with the reestablishment of Legation Luxembourg.

Legation Luxembourg reopened on September 23, 1944, with Winthrop S. Green as Chargé d’Affaires ad interim. U.S. Ambassador to Belgium Charles Sawyer presented his credentials as Envoy Extraordinary and Minister Plenipotentiary on November 1, 1944; he remained resident at Brussels until November 20, 1945.

Wiley T. Buchanan Jr., presented his credentials as the first U.S. Ambassador to Luxembourg on September 21, 1956.