Largest Disease Outbreaks in US History

The spread of disease is not routinely connected to climate change or the environment. However, ignoring this connection would mean overlooking one important factor in widespread and deadly epidemics. According to NIH research, rain and temperature played a role in the spread of the “Spanish flu” in 1918 and 1919. In a paper titled “The Impact of a Six-Year Climate Anomaly on the “‘Spanish Flu’ Pandemic and WWI,” scientists found that “incessant torrential rain and declining temperatures increased casualties in the battlefields of World War I (WWI), setting the stage for the spread of the pandemic at the end of the conflict.”

The United States has faced numerous major disease outbreaks, with death tolls varying based on historical records, reporting methods, and whether the event was a rapid epidemic or a pandemic that lasted several years.

This Climatecrisis247 ranking lists the most catastrophic outbreaks by estimated U.S. deaths, focusing on infectious diseases and outbreak characteristics such as duration and geography. Some outbreak mortalities are impossible to estimate accurately. Colonial-era smallpox and measles outbreaks among Native Americans caused millions of deaths across the Americas, but precise U.S. figures are unavailable because these outbreaks spread across multiple countries.

Other large-scale epidemics that caused significant deaths in the pre-industrial era included yellow fever (several waves from 1793–1905), cholera (1832–1870s), and typhus (1847 and the following decade). Also excluded, as mentioned above, are European-introduced diseases (smallpox, measles) that killed hundreds of thousands of Native Americans from 1492 onward, causing catastrophic population declines. However, these are not typically quantified as single “U.S.” outbreaks.

Data for this analysis was collected from the CDC National Center for Health Statistics (NCHS), CDC HIV Surveillance Reports, the American Journal of Public Health, and other scientific studies from medical journals.

Interestingly, the two largest outbreaks on the list are among the three most recent. This reveals significant challenges in detecting dangerous diseases that can spread rapidly and preventing their further spread. According to WebMD, “the virus that causes COVID-19 was a novel coronavirus, meaning it had never infected humans. The virus was discovered in Wuhan, China, in 2019 and spread rapidly around the globe. It was declared a pandemic by the World Health Organization in March 2020.” The WHO has estimated the global death toll at 7.1 million.

The COVID-19 pandemic could have been much worse. A vaccine was created within months after the outbreak began. The CDC reports that on December 11, 2020, “FDA issues an EUA for the Pfizer-BioNTech COVID-19 vaccine. ACIP (Advisory Committee on Immunization Practices) recommends the Pfizer-BioNTech COVID-19 vaccine for all people ages 16 years or older for the prevention of COVID-19.” The first U.S. COVID-19 death occurred in February of that year.

The inability to predict or stop the causes of these pandemics means that others could occur. Boston University reports, “According to the global epidemic preparedness coalition CEPI, the chances of another pandemic happening in our lifetimes is about 38 percent.”

1. COVID-19 Pandemic (2020–ongoing) – ~1.2 million deaths (as of late 2025). Deadliest in modern U.S. history; exceeded 1918 flu deaths by 2021. Ongoing but peak waves occurred in 2020–2022. COVID deaths continue at several hundred per week.

2. HIV/AIDS Epidemic (1981–ongoing) – ~700,000–800,000 cumulative deaths. Ongoing epidemic; peak deaths occurred in the 1990s before antiretroviral treatments reduced mortality sharply.

3. 1918 Influenza Pandemic/Spanish Flu (1918–1919) – ~675,000 deaths. Deadliest acute pandemic prior to COVID-19; appeared in waves, killing mostly young adults.

4. Polio Epidemics (1916–1950s, peak 1952) – ~20,000–30,000 total deaths (multiple outbreaks). Series of epidemics; 1952 peak had ~3,000 deaths. Feared due to paralysis in survivors. Eradicated in the U.S. by vaccine.

5. Lower Mississippi Valley Yellow Fever Epidemic (1878) – ~20,000 deaths. One of the worst yellow fever outbreaks; devastated southern cities like Memphis.

6. Asian Flu Pandemic (1957–1958) – ~116,000 deaths. Global pandemic; hit schoolchildren and elderly hardest in U.S.

7. Philadelphia Yellow Fever Epidemic (1793) – ~5,000 deaths. Killed ~10% of Philadelphia’s population; early U.S. public health crisis.

8. Swine Flu (H1N1) Pandemic (2009–2010) – ~12,000–18,000 deaths. Originated in the U.S./Mexico; mostly affected younger people.