A disease of despair is one of three classes of behavior-related medical conditions that increase in groups of people who experience despair due to a sense that their long-term social and economic prospects are bleak. The three disease types are drug overdose, suicide, and alcoholic liver disease.

Suicide is a major national public health issue in the United States. The country has one of the highest suicide rates among wealthy nations. In 2020, there were 45,799 recorded suicides, up from 42,773 in 2014, according to the CDC's National Center for Health Statistics (NCHS). On average, adjusted for age, the annual U.S. suicide rate increased 30% between 2000 and 2020, from 10.4 to 13.5 suicides per 100,000 people. In 2018, 14.2 people per 100,000 died by suicide, the highest rate recorded in more than 30 years. Due to the stigma surrounding suicide, it is suspected that suicide is generally underreported. In April 2016, the CDC released data showing that the suicide rate in the United States had hit a 30-year high, and later in June 2018, released further data showing that the rate has continued to increase and has increased in every U.S. state except Nevada since 1999. From 2000 to 2020, more than 800,000 people died by suicide in the United States, with males representing 78.7% of all suicides that happened between 2000 and 2020. In 2022, a record high 49,500 people died by suicide, while the suicide rate in 2022 reached its highest level since 1941 at 14.3 per 100,000 persons. Surging death rates from suicide, drug overdoses and alcoholism, what researchers refer to as "deaths of despair", are largely responsible for a consecutive three year decline of life expectancy in the U.S. This constitutes the first three-year drop in life expectancy in the U.S. since the years 1915–1918.