Aim: The present study aimed to assess the efficacy of different dental varnishes in prevention of demineralization of enamel along the orthodontic brackets. Materials and methods: A total of 60 premolars that do not have caries and were extracted for orthodontic purposes were used in this study. Transbond™ Plus was used to bond premolar brackets onto the treated surface of enamel. The teeth were then divided into three groups. Group I: Profluorid varnish, group II: CPP-ACP varnish, and group III: Duraflor™ varnish. A Vickers diamond indenter was used to assess the microhardness of the surface of enamel at baseline, fourth day, and seventh day. Results: A slightly meaner surface microhardness (SMH; 334.20 ± 2.10) was seen in group III when compared with group I (332.16 ± 3.02) and group II (330.40 ± 2.02). The mean SMH was 342.02 ± 0.82 in group I on the fourth day which was slightly higher than that of the baseline values, followed by group III (339.48 ± 0.34) and group II (336.64 ± 1.14). No statistically significant differences were noted between the groups. A higher mean microhardness of 349.84 ± 0.66 was seen in group I on the seventh day, followed by group III (342.26 ± 1.08) and group II (338.18 ± 1.08). A statistically highly significant difference was seen between the groups. Conclusion: The present study concluded Profluorid varnish to have maximum potential to reduce demineralization of enamel followed by Duraflor and casein phosphopeptide–amorphous calcium phosphate (CPP-ACP) group. Clinical significance: A most common clinical challenge encountered in orthodontic clinical practice is enamel demineralization or white spot lesion (WSL) development throughout the fixed appliance treatment. Thus, the information about several available varnishes is important to prevent demineralization in regular dental practice.