Background: Dental caries is a prevalent childhood disease that significantly affects oral health and quality of life. Remineralization is a key strategy to reverse early enamel lesions and prevent disease progression. Nanohydroxyapatite (nHA), a biomimetic material with structural similarity to enamel hydroxyapatite (HA), has shown potential as a remineralizing agent. This systematic review evaluates the effectiveness of nHA in remineralizing primary enamel lesions compared to fluoride and nonfluoride agents. Methods: A systematic search was conducted across PubMed, Scopus, Embase, Medline, and Web of Science, following PRISMA guidelines. Studies were selected based on PICOS criteria, and the ROBINS-I tool was used to assess the risk of bias. Primary outcomes included surface microhardness, lesion depth reduction, and enamel integrity. Results: Seven studies met the inclusion criteria. nHA demonstrated comparable remineralization efficacy to fluoride-based agents. Studies using 15 nHA reported superior remineralization outcomes compared to 10, suggesting a dose-dependent effect. However, variations in study protocols and evaluation methods limited direct comparisons. Conclusion: Current evidence suggests that nHA is a promising alternative for remineralizing early enamel lesions in primary teeth, offering efficacy comparable to fluoride-based agents. Further well-designed randomized controlled trials (RCTs) with standardized protocols are needed to establish its optimal use in clinical practice. Clinical significance: nHA may serve as a biocompatible, nontoxic alternative to fluoride for managing primary enamel lesions, contributing to safer and more effective pediatric dental care. © 2025 Elsevier B.V., All rights reserved.