This study investigates the nature, extent, and determinants of substance use among adolescents in five southern Indian states using a mixed-methods approach. Quantitative analysis of 500 participants (mean age = 15.44 years, 94.8% male) revealed high prevalence of tobacco (57.4%) and alcohol (26.8%), with early initiation, gender disparities, and differences across educational status and family structures. Regression analysis identified gender, harm awareness, habitual use, impulse control, and school awareness programs as significant predictors of substance overuse. Findings highlight the need for gender-responsive, context-specific interventions and underscore schools' pivotal role in prevention.