Background <p>Research on adolescent substance use disorders (SUDs) in sub-Saharan Africa has largely overlooked the role of psychopathology, focusing instead on demographic correlates. This study tests a multi-level, mental health-centered framework to explain SUD etiology among Nigerian adolescents, seeking to elucidate psychological pathways and explain an identified rural-urban difference in SUD prevalence.</p> Methods <p>This study is a cross-sectional analysis of data from the Lagos Schools Emotional and Behavioral Health Survey (LSEBHS), a representative sample of 9,441 secondary school students. Multi-level logistic regression was used to examine the contributions of internalizing and externalizing mental health pathways, test for mediation of social stressors, and explore gender-specific risk profiles.</p> Results <p>Mental health comorbidities were the strongest predictors of SUD. Both internalizing and externalizing disorders showed significant independent associations, though internalizing conditions demonstrated the largest effects. Major depressive disorder conferred the highest risk (AOR = 4.89; 95% CI [3.69–6.49]), followed by conduct disorder among externalizing conditions (AOR = 3.40; 95% CI [2.45–4.72]). The internalizing pathway was particularly pronounced among females (AOR = 6.83 for depression). Mental health conditions significantly mediated the effect of academic stress on SUD risk. The elevated prevalence of SUD in rural areas was explained by a greater clustering of untreated mental health burden and family violence. A cumulative risk index identified that 16.8% of adolescents fell into a high-risk category.</p> Conclusion <p>Adolescent SUD in Nigeria appears to be driven primarily by underlying psychological distress. These findings suggest the need for a paradigm shift in prevention, moving from universal drug education toward integrated, gender-sensitive mental health screening and intervention, particularly in underserved rural communities.</p>