The United States recognized the independence of Tajikistan on December 25, 1991, following the Dissolution of the Soviet Union.

Diplomatic relations between the two countries were established on February 19, 1992[1] In March 1992, the U.S. Embassy in Dushanbe was opened, headed by interim Chargé d'Affaires of the U.S., Edmund McWilliams, at the "Avesto" hotel.

[1][3] On October 25, 1992, six days after Ambassador Escudero's arrival, the American embassy in Tajikistan was temporarily closed, and all staff were evacuated due to the Tajikistani Civil War.

[1] From 1998 to 2006, the U.S. Embassy operated from the ambassador's residence on Pavlova Street, and dozens of American staff members split their time between Almaty and Dushanbe.

[5] In August 2021, the embassy rejected a request by Markwayne Mullin for assistance to illegally enter Afghanistan with a large amount of cash.