Psychotherapeutic treatment of adolescents requires age-specific approaches and thus plausibly also involves different change mechanisms than adult psychotherapy. To guide further research and improve therapeutic outcomes for adolescents, we reviewed all RCTs investigating mechanisms of change in the psychological treatment of adolescents to identify the most promising age-, disorder- or treatment-specific mediators. Following the preferred reporting items for systematic reviews (PRISMA), 106 studies were included that reported 252 statistical mediation tests assessed with 181 different measures. Most often studied and significant mediators were cognitive, followed by family-related, and behavioral variables. Several mediators were identified to be promising for future investigations: changes in negative thoughts, dysfunctional beliefs and metacognitive skills; family functioning and parenting skills; as well as successful engagement in therapy activities and increased impulse control. Symptom change during therapy was least often a mediator for other therapeutic changes. Relational and emotional mediators were largely understudied, whereas peer-influence appeared a promising mediator for intervention outcomes. Adolescence-specific mediators were most commonly investigated. Majority of studied mediators were not disorder-specific. There was a tendency to mainly test change mechanisms of specific theoretical models without considering other possible change theories. Further, virtually no studies fulfilled all criteria for rigorously investigating mediation and only nine were classified with an overall good study quality. While bearing in mind the current limitations in study designs, methodological rigor and reporting, there appears to be substantial evidence for transdiagnostic age-specific change models in the psychological treatment of adolescents. For future research, need for consensus on a core set of transdiagnostic and transtheoretical mediators and measures is highlighted. These should address likely core mechanisms of change, as well as take into account age-relevant developmental challenges and biological markers.