Adolescents are susceptible to developing depression and anxiety, and educational interventions could improve their mental well-being. This systematic review aimed to evaluate the effectiveness of universal educational prevention interventions in improving mental health literacy, depression, and anxiety among adolescents. Eight electronic databases were searched until June 2024: Cochrane Library, PubMed, EMBASE, CINAHL, PsycINFO, Scopus, Web of Science, ProQuest Dissertations, and Theses Global. Since the included studies assessed various aspects of mental health literacy, the results for mental health literacy were synthesized narratively. In contrast, a meta-analysis using a random-effects model was applied to the depression and anxiety outcomes. Heterogeneity was examined using I<sup>2</sup> statistics and Cochran's Q Chi-squared test. The Cochrane risk of bias tool and the GRADE approach conducted quality appraisal at the study and outcome levels, respectively. The review was reported according to the PRISMA guidelines. This review included 34 randomized controlled trials. Universal education prevention interventions were found to be promising in improving adolescents' mental health literacy but showed limited effects on individual mental health literacy components and on reducing depression (SMD = -0.06, 95%CI: [-0.11, -0.02], Z = 2.58, p = 0.01, I<sup>2</sup> = 45%) and anxiety (SMD = -0.00, 95%CI: [-0.06, 0.06], Z = 0.07, p = 0.94, I<sup>2</sup> = 58%) at post-intervention. Future trials should consider using a hybrid delivery model utilizing health care and the non-health care professionals. These interventions must incorporate skills-based sessions to develop emotional regulation strategies, complemented by extended follow-up periods that include booster sessions to reinforce learning. Given the very low quality of evidence as rated by the GRADE approach, current findings need to be interpreted with caution.
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