U.S. labor markets have experienced transformative change over the past half century. Spurred on by global economic change, robotization, and the decline of labor unions, state labor markets have shifted away from an occupational regime dominated by the production of goods to one characterized by the provision of services. Prior studies have proposed that the deterioration of employment opportunities may be associated with the rise of substance use disorders and drug overdose deaths, yet no clear link between changes in labor market dynamics in the U.S. manufacturing sector and drug overdose deaths has been established. Using restricted-use vital registration records between 1999 and 2017 that comprise over 700,000 drug deaths, I test two questions: First, what is the association between manufacturing decline and drug and opioid overdose mortality rates? Second, how much of the increase in these drug-related outcomes can be predicted by manufacturing decline? The findings provide strong evidence that the restructuring of the U.S. labor market has played an important upstream role in the current drug crisis. Up to 92,000 overdose deaths for men and up to 44,000 overdose deaths for women are predicted by the decline of state-level manufacturing over this nearly two-decade period. These results persist in models that adjust for other social, economic, and policy trends changing at the same time. Critically, the findings signal the value of policy interventions that aim to reduce persistent economic precarity experienced by individuals and communities, especially the economic strain placed upon the middle class.