This systematic review aimed to identify school-based interventions for ensuring mental health and well-being of adolescents, synthesize existing interventions, and summarize the quality of identified studies. A systematic review, analysis, and synthesis were performed. Search was performed in Cochrane Library, PsychARTICLES, Web of Science, CINAHL, and Medline. Literature search was performed in March 2019 using inclusion and exclusion criteria. PRISMA guidelines were followed. Identified records were reviewed by title, abstract, and by the full text by two independent researchers. Three authors independently made a quality assessment of the included studies. Included studies were extracted and synthesized. A systematic review was registered in PROSPERO (CRD42019128919). The initial search yielded 1,199 articles. Of them, 57 articles were included in the final analysis and synthesis. Only four studies were assessed as high quality. Identified themes were mental health and well-being, positive psychology, problem-solving and stress reduction, mindfulness, and physical activity. More than half (N = 32, 56.14%) interventions showed a positive outcome after implementation. Most of those interventions focused on positive psychology and mindfulness. Mental well-being is important for the healthy development of adolescents. Countries are aware that healthy adolescents will become healthy adults who will contribute to his/her community and will lower costs of the absence of work and treatments. Thus, they support and invest in interventions that prevent mental disorders. There is a need for developing multidimensional mental well-being interventions that are effective in low- and secondary-income countries. This study ensured rigorous methodology, followed PRISMA recommendations and evaluated quality of identified literature using the GRADE guidelines. A critical synthesis was performed to produce an integrated conceptualization of the evidence. The synthesis represents a list of effective school interventions for the promotion of adolescents' mental well-being.