Background: Adolescence and young adulthood is a risk period for the emergence of mental disorders. There is strong evidence that psychotherapeutic interventions are effective for most mental disorders. However, very little is known about which of the different psychotherapeutic treatment modalities are effective for whom. This large systematic review aims to address this critical gap within the literature on non-specific predictors and moderators of the outcomes of psychotherapeutic interventions among adolescents and young adults with mental disorders. Methods: The protocol is being reported in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) Statement. PubMed and PsycINFO databases will be searched for randomized controlled and quasi-experimental/naturalistic clinical trials. Risk of bias of all included studies will be assessed by the Mixed Methods Appraisal Tool. The quality of predictor and moderator variables will be also assessed. A narrative synthesis will be conducted for all included studies. Discussion: This systematic review will strengthen the evidence base on effective mental health interventions for young people, being the first to explore predictors and moderators of outcome of psychotherapeutic interventions for a wide range of mental disorders in young people. Systematic review registration: PROSPERO CRD42020166756.