Drug mortality risks vary among industries, creating distinctive geographic patterns across US counties. However, less is known about how local labor market structure relates to drug overdose mortality amid the synthetic opioid era in the United States. This study investigates the relationship between industry-specific job composition and drug overdose mortality at the county level while exploring how fentanyl's presence in illicit drug supplies may moderate the relationship. Data were derived from the National Center for Health Statistics' Multiple Cause of Death files for the rates of drug overdose mortality of any intent, linked with four other sources on industry-specific job shares, drug supply, and county-level sociodemographic characteristics and opioid prescribing rates from the US Census Bureau, the CDC, and the Drug Enforcement Administration. Negative binomial regression models were employed to examine associations between county industry-specific job composition and drug overdose mortality, with tests for moderating effects of state-level fentanyl seizure rates. Our models indicate negative associations between job shares of manufacturing, retail trade, and educational services industries and drug overdose mortality. Positive associations were found for arts/entertainment/recreation and public administration. State-level fentanyl seizure rates had moderating effects on administrative/support/waste management/remediation (A/S/WM/R) and educational services. Counties with a higher concentration of arts/entertainment/recreation and public administration jobs need targeted efforts to mitigate drug-related overdose risks. Additionally, areas with higher concentrations of A/S/WM/R service jobs, particularly where fentanyl seizure rates are higher, may require proactive harm reduction strategies for reducing overdose risks.