Dental caries remains a prevalent chronic disease driven by dysbiosis in the oral biofilm, with Streptococcus mutans playing a central role in its pathogenesis. Objective: This study aimed to assess the effect of D-tagatose on cariogenic risk by analyzing randomized clinical trials (RCTs). Methods: A systematic literature review was conducted targeting RCTs published up to 2024 in eight databases and two gray literature sources. The search strategy utilized Medical Subject Headings (MeSHs) and relevant keywords combined via Boolean operators using the query "Tagatose OR D-tagatose AND Dental Caries". Eligible studies must evaluate the impact of D-tagatose on cariogenic risk, as indicated by reductions in colony-forming units (CFUs) and improvements in salivary pH levels in treatment groups. Results: From 1139 retrieved records, three studies met the inclusion criteria. These studies consistently demonstrated significant reductions in CFU counts and improvements in salivary pH levels in groups treated with D-tagatose compared to controls using other non-caloric sweeteners or placebos (p < 0.01). However, the quality of the evidence was heterogeneous, with certain methodological concerns. Conclusions: Although the findings suggest potential benefits of D-tagatose in reducing cariogenic risk, limitations such as small sample sizes and variability in study methodologies warrant caution. Further robust investigations are needed to substantiate these promising results and support the integration of D-tagatose into oral care formulations aimed at reducing cariogenic risk.