Mindfulness interventions have increasingly been incorporated in elementary and high school classrooms to support students’ mental health and well-being; however, there is little research examining the specific factors contributing to the effectiveness of the interventions. The purpose of this meta-analysis was to examine the specific effects of and moderators contributing to school-based mindfulness interventions for mental health in youth. A systematic review of studies published in PsycINFO, ERIC, Social Work Abstracts, Social Services Abstracts, and CINAHL was conducted. A total of 24 studies (n = 3977) were included in the meta-analysis. Overall, mindfulness interventions were found to be helpful, with small to moderate significant effects pre-post intervention compared to control groups (Hedges’ g = 0.24, p < .001); however, interventions that were delivered during late adolescence (15–18) and that consisted of combinations of various mindfulness activities had the largest effects on mental health and well-being outcomes. Furthermore, the effects on specific mindfulness and mental health outcomes differed according to whether the intervention was delivered by an outside facilitator compared to trained educators/teachers. These results suggest that individual differences and program characteristics can impact receptivity and effectiveness of mindfulness training. These findings represent a significant contribution as they can be used to inform future designs and applications of mindfulness interventions in the school setting.