Following its independence from Spain in 1821, Guatemala joined the Federation of Central American States in 1823 along with Honduras, Nicaragua, Costa Rica, and El Salvador.

The United States recognized the Federation of Central America and the diplomatic relations with Guatemala were established when President James Monroe received Antonio José Cañaz as Envoy Extraordinary and Minister Plenipotentiary on August 4, 1824.

On May 4, 1943, the Guatemalan Legation in the United States was raised to Embassy with Adrian Recinos as Envoy Extraordinary and Minister Plenipotentiary.

The United States remains one of the major trading partners of Guatemala, there are strong political and cooperation ties between the two countries.

The main concerns in the Guatemala-United States bilateral relationships are: Regional Security Initiative for Central America (CARSI), National Police and Public Ministry, adoptions, International Commission against impunity in Guatemala (CICIG), Human Rights, institutionalization of project FIAAT and TPS (Temporary Protected Status).