Background: Adolescents and young adults in the United States have experienced substantial increases in substance use, depressive symptoms, and suicide-related behaviors after the COVID-19 pandemic. However, evidence remains limited on how alcohol, opioid, and polysubstance use co-occur with severe depressive disorder and suicidality. This study examined these associations and identified high-risk subgroups using nationally representative post-pandemic data.

Methods: We conducted a cross-sectional secondary analysis of publicly available National Survey on Drug Use and Health data among adolescents and young adults aged 12–29 years. Survey weights and design variables were applied to generate nationally representative estimates. Weighted prevalence estimates described substance use and mental health outcomes, and prevalence ratios and multivariable logistic regression models were used to examine associations between substance use categories and severe depressive disorder and suicide-related outcomes, adjusting for sociodemographic and pandemic-related factors.

Results: Overall, 40.9% of participants reported at least one adverse mental or behavioral health outcome. Symptoms of anxiety or depression were reported by 30.9%, increased substance use by 13.3%, and suicidal ideation by 10.7%. Young adults aged 18–24 years experienced the highest burden, including anxiety or depressive symptoms (62.9%) and suicidal ideation (25.5%). Unpaid adult caregivers demonstrated particularly elevated risk, with increased substance use reported by 32.9% (PR 5.28, 95% CI 4.59–6.07) and suicidal ideation by 30.7% (PR 8.64, 95% CI 7.23–10.33). Longitudinal analyses showed more than threefold higher odds of incident substance use (adjusted OR 3.33, 95% CI 1.75–6.31) and suicidal ideation (adjusted OR 3.03, 95% CI 1.20–7.63) among caregivers.

Conclusions: Substance use, especially alcohol, opioids, and polysubstance involvement, is closely linked to severe depression and suicide risk among U.S. adolescents and young adults, highlighting the need for coordinated prevention efforts that address mental health, substance use, and social stressors together.