BACKGROUND: Previous research has shown an association between psychological distress and overdose death among specific populations. However, few studies have examined this relationship in a large US population-based cohort. METHODS: Data from the 2010-2018 NHIS were linked to mortality data from the National Death Index through 2019. Psychological distress was measured using the Kessler 6 scale. Drug overdose deaths were examined, and deaths from all other causes were included as a comparison group. Cox proportional hazards regression was used to estimate mortality risk by psychological distress level. RESULTS: The study population included 272,561 adults. Adjusting for demographic covariates and using no psychological distress as the reference, distress level was positively associated with the risk of overdose death: low (HR = 1.8, 95 % CI = 1.1-2.8), moderate (HR = 4.1, 95 % CI = 2.5-6.7), high (HR = 10.3, 95 % CI = 6.5-16.1). A similar pattern was observed for deaths from all other causes: low (HR = 1.2, 95 % CI = 1.1-1.2), moderate (HR = 1.9, 95 % CI = 1.7-2.0), high (HR = 2.6, 95 % CI = 2.4-2.8). LIMITATIONS: Limited substance use information prevented adjustment for this potentially important covariate. DISCUSSION: Adults with psychological distress were at greater risk of drug overdose death, relative to those without psychological distress. Adults with psychological distress were also at increased risk of death due to other causes, though the association was not as strong.