More Americans could lose their lives to deaths of despair, deaths due to drug, alcohol, and suicide, if we do not do something immediately. Deaths of despair have been on the rise for the last decade, and in the context of COVID-19, deaths of despair should be seen as the epidemic within the pandemic. The goal of this report is to predict what deaths of despair we might see based on three assumptions during COVID-19: economic recovery, relationship between deaths of despair and unemployment, and geography. Across nine different scenarios, additional deaths of despair range from 27,644 (quick recovery, smallest impact of unemployment on deaths of despair) to 154,037 (slow recovery, greatest impact of unemployment on deaths of despair), with somewhere in the middle being around 68,000. However, these data are predictions. We can prevent these deaths by taking meaningful and comprehensive action as a nation.