In this paper, we study how the opioid epidemic influenced local population growth in the United States. Exploiting variation in exposure to the epidemic—driven by Purdue Pharma’s targeted marketing of OxyContin and proxied by 1996 cancer mortality rates—we find that commuting zones with greater exposure experienced significant population declines. By 2020, areas more exposed to the epidemic experienced 2.5 percentage points lower population growth per one–standard-deviation increase in exposure, and this reduced growth was concentrated among individuals aged 18 to 44. Direct mortality from drug-induced deaths made only a limited contribution to these changes, particularly during the first decade of the epidemic. Instead, population losses were primarily driven by shifts in migration patterns: exposure increased out-migration rates, especially among women and college-educated individuals. We also document a rise in fertility that, by 2020, partially offset population losses among individuals under 18. Taken together, our findings show that the epidemic reshaped local demographic composition and contributed to the long-run divergence in population dynamics across U.S. commuting zones.