Despite an increased risk of mental health problems in adolescents with autism spectrum disorder (ASD), there is limited research on effective prevention approaches for this population. Funded by the Cooperative Research Centre for Living with Autism, a theoretically and empirically supported school-based preventative model has been developed to alter the negative trajectory and promote wellbeing and positive mental health in adolescents with ASD. This conceptual paper provides the rationale, theoretical, empirical and methodological framework of a multilayered intervention targeting the school, parents and adolescents on the spectrum. Two important interrelated protective factors have been identified in community adolescent samples, namely the sense of belonging (connectedness) to school and the capacity for self and affect regulation in the face of stress (i.e. resilience). We describe how a confluence of theories from social psychology, developmental psychology and family systems theory, along with empirical evidence (including emerging neurobiological evidence), supports the interrelationships between these protective factors and many indices of wellbeing. However, the characteristics of ASD (including social and communication difficulties, and frequently difficulties with changes and transitions, and diminished optimism and self-esteem) impair access to these vital protective factors. The paper describes how evidence-based interventions at the school level for promoting inclusive schools (using the Index for Inclusion) and interventions for adolescents and parents to promote resilience and belonging [using the Resourceful Adolescent Program (RAP)] are adapted and integrated for adolescents with ASD. This multisite proof-of-concept study will confirm whether this multilevel school-based intervention is promising, feasible and sustainable.