Childhood and adolescence are crucial periods for developing one’s awareness of sexuality. Comprehensive Sexuality Education (CSE) during these stages is essential for overall growth, fostering healthy self-concepts, and addressing diverse sexual issues among children and adolescents globally. A meta-analysis was conducted to analyze the effectiveness of CSE programs. A literature search was performed on EMBASE, PubMed, CINAHL, Cochrane Library, and PsycInfo for studies published before 14 June 2023, and based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We used the Comprehensive Meta-Analysis (CMA, V4) software version 4.0 for the analysis and interpreted the effect sizes according to Cohen’s definition. Between 2011 and 2020, 21 studies on CSE were published, with the United States having the most publications (17). Of the 34 studies reviewed, 20 were randomized controlled trials. The primary population for CSE was middle/high school students (15), with the most frequent age range being 10–19 years (26). The overall effect size of CSE was significant (effect size = 1.31, p < 0.001), with cognition (effect size = 5.76, p < 0.001) being the most significant. CSE is an effective educational tool for children and adolescents with a significant impact on variables such as cognition and abstinence. It should be incremental from childhood and adolescence to adulthood.