Physical activity is associated with broad physical and psychological benefits in children and adolescents. One construct which may universally characterize functioning across various pediatric populations is health-related quality of life (HRQOL). A number of studies have found positive associations between physical activity and HRQOL; however, to date no systematic review and meta-analysis of physical activity and HRQOL has successfully quantified effects in children and adolescents. A systematic search of PubMed, PsycINFO, and ProQuest Dissertation Abstracts identified 1081 relevant, non-duplicate articles. Out of these possible articles, 33 studies, including both descriptive and pre-post intervention designs, met inclusion criteria and were included in effect size analyses. In descriptive studies, there was a small, positive effect of physical activity on HRQOL based on child-reports (Hedge's g = .302, p < .001) and a negligible effect based on parent-proxy reports (Hedge's g =.115, p =.101). In intervention studies, there was a small, positive effect of physical activity intervention on HRQOL based on child-reports (Hedge's g = .279, p = .014) and a medium, positive effect based on parent-proxy reports (Hedge's g = .522, p = .012). However, effects are attenuated by removal of a single intervention study. Overall, these findings supported the primary hypothesis that increased levels of physical activity would be related to better HRQOL in youth, although the magnitude of these effects did not represent a minimal clinically important difference (MCID) in most studies. Hypothesized moderators, including chronic disease status, weight status, sex, and study rigor, did not significantly moderate the relationship between physical activity and HRQOL. Exploratory analyses did not find intervention contact hours or age to moderate the effect of exercise on HRQOL. Future studies are needed to assess HRQOL in youth before and after high-quality exercise interventions to quantify the type, frequency, iv duration, and intensity of physical activity needed to change HRQOL to a clinically meaningful level. Although effects were small and analyses were limited, this study represents the first meta-analysis of physical activity and HRQOL across pediatric populations and may serve as a guide for future studies.