This study investigates the role of fading economic opportunity in two significant trends faced by working-age adults in the United States: worsening mortality (particularly from drug overdoses) and rising rates of application to the Social Security Disability Insurance (SSDI) and Supplemental Security Insurance (SSI) programs. Specifically, we examine the relationship between commuting zone-level exposure to automation which has led to reductions in labor-market opportunities in historically important sectors such as manufacturing—and county-level mortality and SSI/SSDI application rates for 18–65-year-olds. Using exogenous variation in automation (as measured by the penetration of industrial robots per 1,000 workers) to support causal inference, we find that increases in automation over the period 1993–2007 led to substantive increases in drug overdose mortality for both men and women, particularly in manufacturing counties. The largest impacts were for 30–44 and 45–54-year-old men living in manufacturing counties, for whom we also find significant increases in mortality from all causes and suicide. We also find strong effects of automation on SSDI and SSI applications, driven by applications that were ultimately denied. Collectively, the average increase in automation exposure can account for 12% of the rise in drug overdose mortality between 1993 and 2007, and 22% and 12% of the rise in SSI and SSDI applications, respectively, between 2000 and 2007. We also find meaningful heterogeneity in the relationship between automation and drug overdose mortality: counties with higher levels of social capital and higher shares of college graduates experienced fewer drug overdose deaths for similar levels of exposure to automation, as did counties in states with more generous Medicaid programs. Counties in states with lower rates of opioid prescriptions also experienced larger increases in mortality from automation.