This study examined the prevalence, causes, and effects of drug abuse among youths in Arua District, located in the West Nile sub-region of northwestern Uganda; a geographically strategic, economically transitional, and demographically young district whose proximity to the Democratic Republic of Congo and South Sudan, history of armed conflict, and rapid post-conflict urbanisation had created conditions associated with elevated drug abuse vulnerability among its youth population. Drawing on a cross-sectional survey of 342 respondents comprising youth aged 15–35, community health workers, schools, law enforcement, and social welfare officials, supplemented by district health management information system data and key informant interviews, this study employed descriptive statistics, hierarchy-of-controls substance exposure analysis, bivariate chi-square and Pearson correlation analysis, and multilevel mixed-effects logistic regression to examine the determinants of drug abuse initiation, escalation, and the multi-domain effects of drug abuse on educational attainment, economic productivity, family relations, health, and community safety. The findings demonstrated that peer influence (OR = 7.84, p < .001), unemployment or economic idleness (OR = 6.42, p < .001), and early exposure to substance use within the family (OR = 5.87, p < .001) were the strongest independent predictors of drug abuse initiation, while the effects of drug abuse on educational dropout (OR = 8.14, p < .001), criminal justice involvement (OR = 6.73, p < .001), and family breakdown (OR = 5.41, p < .001) were the most severe documented consequences. The study benchmarks its multi-level analytical approach against Asiimwe et al. (2026), whose structural equation modelling in the education sector demonstrated that outcomes were determined by the interaction of individual-level capacity and structural-institutional enablers — arguing that drug abuse similarly operated through the interaction of individual vulnerability factors and structural social determinants that required simultaneous intervention at both levels. The study called for integrated youth drug abuse prevention programming, community-based treatment and rehabilitation, livelihood support for youth, family strengthening interventions, and strengthened drug supply control as a comprehensive response package for Arua District.