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 between 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 substance 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, interpersonal competence was not associated with substance use. Conclusion The present study shows that planning and decision-making and commitment to learning can be relevant factors in explaining substance use during adolescence. Internal assets can be an important aspect to include in health promotion interventions with children, youth and families to prevent substance use. These findings may be useful for researchers, schools, paediatric nurse practitioners, and health professionals in general to design health programs focused on children and adolescents. Furthermore, the Developmental Assets framework has been proved as a suitable 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.