Background This randomized controlled trial aimed to compare the efficacy of silver diamine fluoride (SDF) and Casein Phosphopeptide-Amorphous Calcium Phosphate fluoride Varnish (CPP-ACPFV) in preventing caries development, enamel breakdown, and sensitivity on molars affected by molar incisor hypomineralization (MIH) in children. Methods A total of 100 children aged 6 to 9 years were enrolled in the study with two contralateral permanent molars mildly affected by MIH. Affected molars were randomly and equally assigned to receive either SDF or CPP-ACPFV treatment. The interventions were applied at four different time points (baseline, 3, 6, 9 months), and the incidence of caries, caries progression, enamel breakdown, and sensitivity were assessed. Results The findings of this study revealed significant differences in the incidence of caries between the groups treated with SDF and CPP-ACPFV (P-value < 0.05). Similarly, there was a significant difference in caries progression between the two groups (P-value < 0.05). However, no significant differences were observed in enamel breakdown scores between the treatment groups, as the majority of teeth in both groups exhibited a score of 0. Furthermore, there were no significant differences in sensitivity between the treatment groups throughout the study period. Conclusions In conclusion, the results of this study provide evidence that molars treated with SDF demonstrated a lower incidence of caries and a higher rate of caries arrest compared to those treated with CPP-ACPFV. Both interventions showed promise in preventing enamel breakdown and improving sensitivity. These findings highlight the potential of SDF and CPP-ACPFV as effective treatments for caries prevention and management, emphasizing the importance of early intervention and appropriate dental care strategies in maintaining oral health. Trial registration ISRCTN54243749 (13/01/2022).