BACKGROUND: Mindfulness training (MT) for parents of adolescents has been shown to improve mental health and stress-related outcomes in individuals and their families. Studies of MT among young people are mainly delivered in educational or clinical settings, and there is a need for controlled studies on both parent-directed and adolescent-directed approaches. It is unclear whether MT has preventive effects for substance use outcomes. The primary objective of this trial is to evaluate the effectiveness of family-based MT targeting both adolescents and their parents to prevent adolescent substance use and enhance neurobehavioral self-regulation skills that play a major role in addiction development and mental health. METHODS/DESIGN: The trial design is a superiority, two-arm, randomized controlled trial in which families will participate either in the full curriculum of the evidence-based Strengthening Families Program 10-14 (SFP 10-14, German adaptation) or in a mindfulness-enhanced version of this program (SFP-Mind). Both seven-session interventions are highly structured and will each be delivered over a period of approximately 7 weeks. The experimental intervention SFP-Mind is a modified version of the SFP 10-14 in which some elements were eliminated or changed to enable the inclusion of additional parent-directed and adolescent-directed mindfulness components. The primary outcome is adolescent self-reported alcohol use based on an alcohol initiation index at 18-month follow-up. Dispositional mindfulness, impulsivity, and emotion regulation will be included as secondary outcomes and potential mechanisms of action. The study will recruit and randomize 216 adolescents, aged 10-14 years, and their parents who will be followed up for 18 months. DISCUSSION: This trial aims to evaluate the effectiveness of SFP-Mind for family-based prevention of substance use and promoting mental health in adolescence. TRIAL REGISTRATION: German Register of Clinical Studies, DRKS00015678. Registered on 25 February 2019.