Aims: To determine the associations between internal assets (planning and decision- making, interpersonal competence and commitment to learning) and substance use (tobacco, alcohol, binge drinking, marijuana use and other drugs).Design: A cross-sectional study was conducted in four countries (Chile, Mexico, Spain and Peru).Methods: Adolescents aged 12–18 self-completed a multi-purpose questionnaire be-tween 2016 and 2019. Multiple logistic regressions and structural equation models were performed to analyse the association between internal assets (planning and decision- making, interpersonal competence, and commitment to learning) and sub-stance use.Results: The results indicate that planning and decision- making and commitment to learning are conducive to the prevention of substance use. On the contrary, interper-sonal competence was not associated with substance use.Conclusion: The present study shows that planning and decision- making and com-mitment to learning can be relevant factors in explaining substance use during ado-lescence. Internal assets can be an important aspect to include in health promotion interventions with children, youth and families to prevent substance use. These find-ings may be useful for researchers, schools, paediatric nurse practitioners, and health professionals in general to design health programs focused on children and adoles-cents. Furthermore, the Developmental Assets framework has been proved as a suit-able frame of reference for paediatric nurse practitioners to assess and develop child and adolescent positive development and design health promotion interventions to prevent substance use.