<p>Drug and alcohol overdose deaths represent a growing public health crisis in the United States. While previous research has shown that lower individual socioeconomic status is associated with increased overdose risk, less is known about how area-level socioeconomic conditions contribute to overdose mortality. This study examined the relationship between county-level social vulnerability and overdose death rates. We analyzed national overdose death data (<i>n</i> = 967,546) from 1999 to 2020 obtained from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research. County-level age-adjusted mortality rates (AAMRs) were examined in relation to the Social Vulnerability Index (SVI), a validated composite measure of area-level socioeconomic status (range 0–1, with higher scores indicating greater vulnerability). Counties were stratified into SVI quartiles, and trends in overdose mortality were assessed overall and by race. The overall AAMR from drug and alcohol overdose was 14.33 per 100,000 (95% CI 14.30–14.36). Higher SVI was significantly associated with increased overdose mortality (<i>p</i> &lt; 0.001). When stratified by race, increasing SVI was associated with higher overdose death rates among White people (<i>p</i> = 0.003) but not among Black people (<i>p</i> = 0.89). In the most recent decade (2011–2020), the association between SVI and overdose mortality weakened and was no longer statistically significant (<i>p</i> = 0.07). Overdose deaths continue to rise nationally, with greater burdens in more socially vulnerable communities. However, the diminishing association between social vulnerability and overdose mortality in recent years suggests that the crisis is increasingly widespread across sociodemographic groups. Public health interventions must extend beyond traditionally defined high-risk areas to address the evolving and pervasive nature of the overdose epidemic.</p>