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Schools are central to substance use prevention efforts for young people, yet program effectiveness remains inconsistent, and education sector perspectives are underrepresented in prevention science. This overview of systematic reviews and meta-analysis synthesizes global evidence on school-based substance use programs for youth aged 5–18, focusing on intervention effectiveness by developmental stage, prevention level, and school health components. Guided by the Health Promoting Schools framework and UN prevention standards, findings show small short-term reductions in tobacco use but minimal impacts for alcohol, cannabis, and illicit drugs. We call for future-oriented, whole-school approaches that move beyond abstinence-focused models toward integrated, equity-informed strategies that reflect the histories of education-health collaboration and reimagine prevention for student wellbeing.