Background <p>Adverse childhood experiences (ACEs) have been associated with a number of detrimental outcomes in adolescence. The relationship between ACEs and substance use behaviors is poorly characterized among clinical inpatient samples, although this population may be at most need for effective intervention.</p> Objective <p>To address this gap in the literature, the present study comprehensively examined correlates of substance use behavior in a sample of adolescent inpatients undergoing psychiatric hospitalization, with emphasis on the role of ACEs.</p> Method <p>A retrospective review of medical records spanning from 2019 to 2023 included 551 participants (54.8% female, 67.3% non-Hispanic white) between the ages of 13 to 21, who underwent comprehensive neuropsychological evaluation while hospitalized in an inpatient psychiatric unit. Participants were classified as substance users and non-substance users and psychiatric diagnoses were assigned based on clinical interview. Regression models examined the relationship between overall ACE score, individual ACEs, and substance use, adjusting for covariates.</p> Results <p>Participants most commonly reported experiencing 7 ACEs. 40.3% of the sample were classified as substance users (<i>n</i> = 222). Substance users were found to have a higher number of total ACEs. The odds of substance use increased by 10.4% with each additional ACE history (aOR = 1.102, 95% CI [1.143–1.432], <i>p</i> &lt; 0.001). The significant association between ACEs and substance use remained when adjusting for a post-traumatic stress disorder diagnosis.</p> Conclusions <p>Results underscore the pervasive impact of ACEs on substance use behaviors among clinically acute adolescents undergoing hospitalization. Findings highlight the role of early-life stressors in shaping substance use behaviors among adolescents in psychiatric care.</p>