Background Mental and substance use disorders are among the leading causes of burden of disease worldwide, with risk of onset peaking between the ages of 13 and 24 years. Comorbidity is also common among young people and complicates research, diagnosis and assessment, and clinical decision making. There is increasing support for empirically derived models of psychopathology that overcome issues of comorbidity and provide a transdiagnostic framework for investigating the specificity and generality of risk and protective factors for psychopathology. Objective This systematic review aims to identify transdiagnostic risk and protective factors for psychopathology in young people by synthesizing and evaluating findings from research investigating empirically based models of psychopathology. Methods Searches will be conducted in Medline, EMBASE, and PsycINFO databases. Reference lists of selected articles will also be hand searched for other relevant publications. All studies will be screened against eligibility criteria designed to identify studies that examined empirical models of psychopathology in relation to risk and/or protective factors in young people with a mean age between 10 and 24 years. Study quality will be assessed using the Joanna Briggs Institute Critical Appraisal Checklists for Cohort Studies and Analytical Cross-Sectional Studies. Findings will be summarized in a narrative synthesis, and a meta-analysis will be conducted if sufficient data are available. Results This review is ongoing. At the time of submission, full-text screening was completed, and hand searching of selected articles was underway. Results are expected to be completed by the end of 2020. Conclusions This protocol is for a systematic review of evidence for transdiagnostic risk and protective factors associated with empirically based models of psychopathology in young people. To our knowledge, the critical synthesis of this evidence will be the first to date and will provide a better understanding of the factors that contribute to the onset and maintenance of psychopathology in young people. Insights drawn from the review will provide critical new knowledge to improve the targeting of interventions to prevent or reduce mental health problems. Trial Registration This systematic review is registered with PROSPERO (CRD42020161368) and is available via Open Science Framework. International Registered Report Identifier (IRRID) DERR1-10.2196/19779