We investigated the mediating role of alcohol use expectancies between three psychological/emotional states (depressive symptoms, hopelessness, and adverse childhood experiences (ACE)) and problematic alcohol and substance use among YLHIV in Uganda. We defined problematic substance use according to the National Institute on Drug Abuse (NIDA)-modified Alcohol, Smoking, and Substance Involvement Screening Test (NM-ASSIST) to derive a Substance Involvement (SI) score to identify participants' risk level. We grouped moderate and high risk into one category to represent 'problematic use' or use that would qualify as a substance use disorder. We tested the proposed mediation models using the PROCESS macro for mediation, moderation, and conditional process analysis version 4.1 for SPSS. We observed that higher scores for depressive symptoms, hopelessness, and ACE, were each associated with increased levels of global AUE (GAUE). However, mediation analyses revealed significant indirect effects of depressive symptoms (1.03, 95% CI 1.0002 to 1.0926), hopelessness (1.11, 95% CI 1.0172 to 1.3349), and ACE (1.08, 95% CI 1.0027 to 1.2695) on problematic substance use via GAUE. Also negative AUE (NAUE) significantly mediated the relationship between depressive symptoms, hopelessness, and ACE and problematic substance use. Our study highlights the significant role of GAUE and NAUE in mediating the relationship between ACE, depressive symptoms, hopelessness, and problematic substance use among YLHIV. The findings suggest that interventions targeting GAUE and NAUE and possibly providing effective coping mechanisms for managing depressive symptoms, hopelessness, and the impact of ACE may be crucial in reducing substance use among YLHIV.