The United States biological defense program—in recent years also called the National Biodefense Strategy—refers to the collective effort by all levels of government, along with private enterprise and other stakeholders, in the United States to carry out biodefense activities.

Biodefense is a system of planned actions to counter and reduce the risk of biological threats and to prepare, respond to, and recover from them if they happen. The National Defense Authorization Act (NDAA) of 2016 required high-level officials across the federal government to create a national biodefense strategy together. As a result, in 2018 the National Biodefense Strategy was released by President Donald J. Trump. In essence, the strategy comprises the U.S. biological defense program in that it is the official framework that provides a "single coordinated effort" to coordinate all biodefense activities across the federal government. To execute the strategy, the White House issued a Presidential Memorandum on the Support for National Biodefense, which puts the specific directives and rules in place for carrying out the plans written in the strategy. The National Biodefense Strategy elevated natural outbreaks as a vital component of the U.S. biological defense program for the first time, mostly because of the significant risk that natural outbreaks pose to civilian, animal and agricultural populations across the country.

The U.S. Biological Defense Program began as a small defensive effort that parallels the country's offensive biological weapons development and production program, active since 1943. Organizationally, the medical defense research effort was pursued first (1956–1969) by the U.S. Army Medical Unit (USAMU) and later, after publicly known discontinuation of the offensive program, by the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID). Both of these units were located at Fort Detrick, Maryland, where the U.S. Army Biological Warfare Laboratories were headquartered. The current mission is multi-agency, not exclusively military, and is purely to develop defensive measures against bio-agents, as opposed to the former bio-weapons development program.

In 1951, due to biological warfare concerns arising from the Korean War, the US Centers for Disease Control and Prevention (CDC) created the Epidemic Intelligence Service (EIS), a hands-on two-year postgraduate training program in epidemiology, with a focus on field work.

Since the 2001 anthrax attacks, and the consequent expansion of federal bio-defense expenditures, USAMRIID has been joined at Fort Detrick by sister bio-defense agencies of the U.S. Department of Health and Human Services (NIAID's Integrated Research Facility) and the U.S. Department of Homeland Security (the National Biodefense Analysis and Countermeasures Center and the National Bioforensic Analysis Center). These—along with the much older Foreign Disease Weed Science Research Unit of the U.S. Department of Agriculture—now constitute the National Interagency Confederation for Biological Research (NICBR).

Broadly defined, the "United States Biological Defense Program" now also encompasses all federal-level programs and efforts to monitor, prevent, and contain naturally occurring infectious disease outbreaks of widespread public health concern. These include efforts to forestall large-scale disasters such as flu pandemics and other "emerging infections" such as novel pathogens or those imported from other countries.

Biological agents have been used in warfare for centuries to produce death or disease in humans, animals, or plants. The United States officially began its biological warfare offensive program in 1941. During the next 28 years, the U.S. initiative evolved into an effective, military-driven research and acquisition program, shrouded in secrecy and, later, controversy. Most research and development was done at Fort Detrick, Maryland, while production and testing of bio-weapons occurred at Pine Bluff, Arkansas, and Dugway Proving Ground (DPG), Utah. Field testing was done secretly and successfully with simulants and actual agents disseminated over wide areas. A small defensive effort always paralleled the weapons development and production program. With the presidential decision in 1969 to halt offensive biological weapons production—and the agreement in 1972 at the international BWC never to develop, produce, stockpile, or retain biological agents or toxins—the program became entirely defensive, with medical and non-medical components. The U.S. biological defense research program exists today, conducting research to develop physical and medical countermeasures to protect service members and civilians from the threat of modern biological warfare.

Both the U.S. bio-weapons ban and the BWC restricted any work in the area of biological warfare to defensive in nature. In reality, this gives BWC member-states wide latitude to conduct biological weapons research because the BWC contains no provisions for monitoring of enforcement. The treaty, essentially, is a gentlemen's agreement amongst members backed by the long-prevailing thought that biological warfare should not be used in battle.