Background/aim: Early childhood caries (ECC) is a prevalent dental disease, influenced by genetic and environmental factors. Human leukocyte antigens (HLA) have been suggested as a predisposing factor. This study aims to estimate and correlate HLA-DR and HLA-DQ activity in the saliva of caries-active and caries-free children, potentially aiding disease diagnosis and prevention. Materials and methods: A comparative study was performed on 50 children, divided into two groups: caries-active and caries-free, consisting of 25 children each, aged 3–6 years. Unstimulated saliva samples were collected and subjected to enzyme-linked immunosorbent assay (ELISA) for analysis. HLA-DR and HLA-DQ levels will be estimated and correlated with caries score, age, and gender. Results: HLA-DR level was 33.032 ± 2.869 pg/mL in the caries-active group and 5.288 ± 0.960 pg/mL in the caries-free group, and was statistically significant at p < 0.001. HLA-DQ isotype level was 5.603 ± 1.264 ng/L in the caries-active group and 4.596 ± 0.748 ng/L in the caries-free group, and was statistically significant at p < 0.001. HLA-DR level showed a statistically significant positive moderate correlation with caries score (p < 0.001), whereas HLA-DQ levels demonstrated a positive very weak correlation with caries score and were not statistically significant. HLA-DQ was statistically significant at p < 0.001 when compared between genders in the caries-active group. Conclusion: Results suggest a substantial correlation between HLA-DR level and the severity of dental caries, and an increase in HLA-DR may be linked to an increase in caries severity. Thus, HLA-DR detection as a molecular biomarker for early diagnosis of ECC may be recommended.