Life Skills (LS) proposes a comprehensive approach to adolescent health in educational settings through the development of socio-emotional and cognitive competencies. In Latin America, adolescents experiment with alcohol at an early age and it is the substance with the highest prevalence rates. According to the literature, LS is an essential theoretical contribution to the field of alcohol and other drug (AOD) prevention, contributing to decision-making about one’s own health and risk reduction. This study presents the characteristics of a protocol based on LS for the prevention of drug use among adolescents in an educational context in Argentina and Brazil. At the same time, the challenges and potential of the pilot implementation for health promotion are being evaluated. High school and university students aged 15–30 years participated. The intervention consisted of 5 sessions that addressed self-awareness, emotions and stress control, empathy and assertiveness, critical thinking and beliefs about drugs, and life project. The results show that the participants had difficulties with self-awareness, conflictual relationships with adults and avoidant coping strategies, which were necessary to cultivate assertiveness. The intervention facilitated group bonding and the need for listening and support spaces, valuing mental health. Contextual factors such as Covid-19, examination periods, the end of the school year and institutional dynamics affected the continuity of activities and reduced the implementation time of the protocol. It is concluded that the pilot intervention helped to understand the potential of the LS approach to prevent AOD use in the school context, as well as to consider the aspects that should be modified and/or taken into account to optimize the implementation of health interventions.