Using a pooled cross-section regression, the study analyzes state-level data on deaths of despair as a function of population health, economic, and demographic indicators identified in the academic literature. There is an urgent need to identify and address factors associated with suicides and deaths attributed to the use of alcohol, opioids, and other drugs and referred to as deaths of despair. According to provisional death data posted on the Centers for Disease Control and Prevention (CDC) website, in the 12-months preceding April 30, 2021, drug overdose deaths increased 28.5 percent compared to the previous year, and alcohol-related deaths rose 34 percent from pre-pandemic levels. These recent increases in death rates are in addition to the rise in suicides and deaths attributable to the use of alcohol, opioids, and other drugs over the past decade. Given the complex, interactive, and synergistic nature of deaths of despair, an approach that incorporates perspectives from public health, economics, and sociology could prove advantageous.