Background: Despite the introduction of several anticaries products, dental caries continues to be a global problem. In recent years, there has been a rise in interest in noninvasive treatment for noncavitated caries lesions by employing remineralization concepts. Each remineralizing agent has its own drawbacks. Therefore, it is desirable to seek new agents that offer the advantages of earlier counterparts with lower detrimental reactions. Aim: The purpose of this research is to evaluate the remineralization efficacy of nanoparticle-based materials on white spot lesion (WSL) in children. Materials and methods: A total of 45 children between the age-group of 4 and 8 years with WSLs were selected and randomly divided into three groups. At baseline, the teeth with WSLs were confirmed and identified using International Caries Detection and Assessment System II (ICDAS II) criteria, and the dimensions of the lesions were measured using photographic methods. Then, they were randomly placed into three groups of 15 samples each—group I nanosilver fluoride (NSF), group II nanohydroxyapatite (nano-HAP) serum, and group III MI varnish. Following that, the varnish was applied, and follow-up was done in the 2nd, 4th, 12th, and 24th week. Results: By the 4th week, all three groups had a statistically significant difference (p < 0.05). Baseline measurements for groups I, II, and III showed that their respective mean WSL dimensions were 4.9 ± 0.66, 4.27 ± 0.69, and 5.44 ± 2.95. The dimensions of each group were reduced by the 24th week to 1.22 ± 0.46, 0.93 ± 0.41, and 2.19 ± 1.40, respectively. Overall, group II (nano-HAP serum) showed a statistically significant decrease in the dimension of the lesion at the end of the 24th week, followed by groups I and III. Conclusion: The remineralization of enamel was induced by all three agents. Nano-HAP serum is more successful than MI Varnish and NSF.