Background: White spot lesions (WSLs), the earliest sign of enamel demineralization, affect up to 50% of children and can progress to caries if untreated. CPP-ACP is a non-invasive remineralizing agent that delivers bioavailable calcium and phosphate to the enamel surface. While its potential is to reverse the course of caries, evidence specific to pediatric populations remains limited. This systematic review evaluates the effectiveness of CPP-ACP in treating WSLs in pediatric patients. Aim: To evaluate the effectiveness of CPP-ACP in the treatment of white spot lesions in pediatric patients. Materials and Methods: A comprehensive electronic search was performed across PubMed, PubMed Central, Google Scholar, EBSCO Host, Scopus, and grey literature from database inception to 17 August 2024. A PubMed search strategy was adapted for all databases using MeSH terms and Boolean operators. Randomized controlled trials (RCTs) evaluating CPP-ACP for treatment of WSLs in children aged 1–15 years were included. In vitro studies, reviews, studies not involving CPP-ACP, and preventive-only orthodontic protocols were excluded. Two reviewers independently screened studies, assessed eligibility, extracted data, and evaluated risk of bias using the Cochrane Risk of Bias 2 (RoB 2) tool. The study selection process followed PRISMA guidelines (PROSPERO: CRD42024580513). Results: A total of 2,807 records were identified; 6 RCTs (n = 377 children) met inclusion criteria. Follow-up ranged from 12 weeks to 12 months. All included studies demonstrated improvement in WSL regression or appearance following CPP-ACP use. Combined CPP-ACP and fluoride formulations generally showed superior outcomes compared with fluoride alone. Varnish-based CPP-ACP achieved faster responses, while daily home-use CPP-ACP produced gradual but sustained improvements. Evidence was strongest for smooth-surface lesions. Conclusion: CPP-ACP is an effective non-invasive therapy for remineralizing white spot lesions in pediatric patients, with enhanced benefit when combined with fluoride. However, heterogeneity in outcome measures, small sample sizes, and variable follow-up durations limit the strength of conclusions. Larger, standardized RCTs with uniform diagnostic criteria are needed..