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Adolescent substance use remains a significant global public health concern, with early initiation associated with adverse mental health outcomes, academic difficulties, and increased risk of substance use disorders later in life. This review examines the role of behavioral health sciences in understanding and preventing adolescent substance use through an interdisciplinary framework integrating psychology, psychiatry, public health, social work, and education. Drawing on established behavioral theories, including Social Learning Theory, Ecological Systems Theory, and the Health Belief Model, the review explores the interaction of individual, family, peer, school, community, and sociocultural factors that contribute to substance use vulnerability. Evidence on cognitive-behavioral mechanisms, mental health comorbidities, peer influence, family dynamics, and adolescent neurodevelopment is synthesized alongside preventive approaches implemented across school, family, community, policy, and digital settings. The review also examines emerging approaches, including trauma-informed prevention, integration of behavioral health into primary care, culturally tailored interventions, and precision prevention using data analytics and personalized risk assessment. Despite advances in prevention, challenges remain regarding implementation capacity, ethical concerns, scalability, sustainability, and the limited availability of longitudinal and cross-cultural evidence. Future directions emphasize hybrid behavioral health and digital models, schools as integrated prevention hubs, stronger policy frameworks, culturally responsive interventions, and longitudinal research aligned with global adolescent health priorities. Overall, the review highlights the importance of multidisciplinary, evidence-based, and context-sensitive prevention strategies that address both individual vulnerabilities and broader environmental determinants of adolescent substance use.