Recent research has implicated economic insecurity in increasing midlife death rates and “deaths of despair,” including suicide, chronic liver disease, and drug and alcohol poisoning. In this ecological longitudinal study, we evaluated the association between changes in economic insecurity and increases in deaths of despair and midlife all-cause mortality in US counties during 2000–2015. We extended a previously developed measure of economic insecurity using indicators from the Census and Federal Reserve Bank in US counties for the years 2000 and 2010. Linear regression models were used to estimate the association of change in economic insecurity with change in death rates through 2015. Counties experiencing elevated economic insecurity in either 2000 or 2010 had higher rates of deaths of despair and all-cause midlife mortality at baseline but similar rates of increase in deaths of despair from 2001 to 2015 compared with counties with stable low economic insecurity. Counties in the highest tertile of economic insecurity in 2000 and 2010 had 41% (95% confidence interval: 1.36, 1.47) higher midlife mortality rates at baseline and a rate of increase of 2% more per 5-year period (95% confidence interval: 1.00, 1.03) than counties with stable low economic insecurity. Economic insecurity may represent a population-level driver of US death trends.