U.S.–Uzbekistan relations formally began when the United States recognized the independence of Uzbekistan on December 25, 1991, and opened an embassy in Tashkent in March 1992.

Relations cooled significantly following the "color revolutions" in the former Soviet republics of Georgia, Ukraine, and Kyrgyzstan in 2003–2005, and the Government of Uzbekistan sought to limit the influence of U.S. and other foreign non-governmental organizations (NGOs) working on civil society, political reform, and human rights inside the country.

Relations improved slightly in the latter half of 2007, but the U.S. continues to call for Uzbekistan to meet all of its commitments under the March 2002 Declaration of Strategic Partnership between the two countries.

Uzbekistan has Central Asia's largest population and is vital to U.S., regional, and international efforts to promote stability and security.

The Departments of State and Defense provide technical assistance in the form of equipment and training to enhance Uzbekistan's control over its borders and its capabilities to interdict the illicit movement of narcotics, people, and goods, including potential weapons of mass destruction-related items.

In FY 2003, the United States provided roughly $87.4 million in humanitarian aid, technical assistance, military-to-military funding, and micro-credit support in Uzbekistan.

Technical assistance to Uzbekistan promotes sound fiscal and management policies, a strengthened business-enabling environment, enhanced competitiveness of the agribusiness sector, increased citizens' participation in civil society and economic decision making, improved sustainability of social benefits and services, reduced environmental risks to public health, and other multi-sector reform programs.

Peace Corps Volunteers were active in English teaching, small business development, public health, and women's issues.

Proceeds from the U.S. Department of Agriculture's Commodity Monetization Program are scheduled to finance more than 30 farmer assistance and rural development projects which were approved jointly by U.S. and Uzbek officials in 2005.

Human rights conditions in Uzbekistan under President Shavkat Mirziyoyev have improved slightly because he wants to assure investors, like the United States, that their investments will not be adversely affected by political instability.

This mixed record and slow progress of human rights improvement is best exemplified in its actions in October 2017: when it freed 5 long-held political prisoners but that same month also arbitrarily detained an author and journalist.

[9] Despite his human rights record, Uzbek President Islam Karimov condemned Saddam Hussein and supported the controversial Iraq War, and continued allowing the U.S. to place troops on the ground as well as use the Uzbek airbase, K2, for support activities and for deployment and command and control of Special Forces into all of Afghanistan except for the Khandahar region.

In August 2024, the United States and Uzbekistan formalised an agreement to form a joint program that would permit the latter country to keep the aircraft with American technical assistance.

[13] U.S. Secretary of State James Addison Baker visited Tashkent and Samarkand on February 16, 1992 and met with Uzbekistan's main opposition party, Birlik, a year after the country's independence from the Soviet Union.

[16] During his visit, Secretary Powell also met with Uzbek Foreign Minister Abdulaziz Komilov and President Karimov to discuss the security of Central Asia.