To examine the effect of universal, school-based, resilience-focused interventions on mental health problems in children and adolescents. Eligible studies were randomized controlled trials (RCTs) of universal, school-based interventions that included strategies to strengthen a minimum of 3 internal resilience protective factors, and included an outcome measure of mental health problems in children and adolescents aged 5 to 18 years. Six databases were searched from 1995 to 2015. Results were pooled in meta-analyses by mental health outcome (anxiety symptoms, depressive symptoms, hyperactivity, conduct problems, internalizing problems, externalizing problems, and general psychological distress), for all trials (5-18 years). Subgroup analyses were conducted by age (child: 5-10 years; adolescent: 11-18 years), length of follow-up (short: post-≤12 months; long: >12 months), and gender (narrative). A total of 57 included trials were identified from 5,984 records, with 49 contributing to meta-analyses. For all trials, resilience-focused interventions were effective relative to a control in reducing 4 of 7 outcomes: depressive symptoms, internalizing problems, externalizing problems, and general psychological distress. For child trials (meta-analyses for 6 outcomes), interventions were effective for anxiety symptoms and general psychological distress. For adolescent trials (meta-analyses for 5 outcomes), interventions were effective for internalizing problems. For short-term follow-up, interventions were effective for 2 of 7 outcomes: depressive symptoms and anxiety symptoms. For long-term follow-up (meta-analyses for 5 outcomes), interventions were effective for internalizing problems. The findings may suggest most promise for using universal resilience-focused interventions at least for short-term reductions in depressive and anxiety symptoms for children and adolescents, particularly if a cognitive-behavioral therapy-based approach is used. The limited number of trials providing data amenable for meta-analysis for some outcomes and subgroups, the variability of interventions, study quality, and bias mean that it is not possible to draw more specific conclusions. Identifying what intervention qualities (such as number and type of protective factor) achieve the greatest positive effect per mental health problem outcome remains an important area for future research. Systematic Review of Universal Resilience Interventions Targeting Child and Adolescent Mental Health in the School Setting; http://dx.doi.org/10.1186/s13643-015-0172-6; PROSPERO CRD42015025908.