All children benefit from intentional interactions and instruction to become socially and emotionally competent. Over the past 30 years, evidence-based intervention tactics and strategies have been integrated to establish comprehensive, multitiered, or hierarchical systems of support frameworks to guide social-emotional interventions for young children. In this study, the authors reviewed systematically the efficacy of classroom-wide social-emotional interventions for improving the social, emotional, and behavioral outcomes of preschool children and used meta-analytic techniques to identify critical study characteristics associated with obtained effect sizes. Four electronic databases (i.e., Academic Search Premier, Educational Resource Information Center, PsycINFO, and Education Full Text) were systematically searched in December 2015 and updated in January 2018. "Snowball methods" were used to locate additional relevant studies. Effect size estimates were pooled using random-effects meta-analyses for three child outcomes, and moderator analyses were conducted. Thirty-nine studies involving 10,646 child participants met the inclusion criteria and were included in this systematic review, with 33 studies included in the meta-analyses. Random-effects meta-analyses showed (a) improvements in social competence and emotional competence, and (b) decreases in challenging behavior. For social competence and challenging behavior, moderator analyses suggested interventions with a family component had statistically significant and larger effect sizes than those without a family component. Studies in which classroom teachers served as the intervention agent produced statistically significant but smaller effect sizes than when researchers or others implemented the intervention for challenging behavior. This systematic review and meta-analysis support using comprehensive social-emotional interventions for all children in a preschool classroom to improve their social-emotional competence and reduce challenging behavior.