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Background and objectives Gestational diabetes mellitus (GDM) increases the chances of negative consequences for both the mother and the foetus. It shares genetic and physiological characteristics with type 2 diabetes mellitus (T2DM), particularly insulin resistance and impaired insulin secretion. While gene variants involved in glucose metabolism, such as those in glucokinase receptor (GCKR) and GLI similar 3 (GLIS3), have been linked to diabetes risk, their association with GDM in South Indian populations remains underexplored. Methods This study comprised 195 patients with GDM and 195 normoglycemic pregnant women of South Indian ethnicity. GDM diagnosis was recognised using an oral glucose tolerance test. Genotyping of GCKR (rs780094) and GLIS3 (rs701847, rs7020673, rs10814916) were performed using Tetra-ARMS PCR and validated through Sanger sequencing. Associations between genotypes and the risk of GDM were assessed using logistic regression. Results Women with GDM exhibited significantly higher age, body mass index, blood pressure, and adverse metabolic profiles. There was a strong genotype-specific correlation between GDM and the GCKR rs780094 CT genotype. When dominant models and the AG genotype were used, rs701847 exhibited the strongest correlation with GLIS3. rs10814916 was linked through the AC genotype, whereas rs7020673 only demonstrated a connection under the recessive model. In women with GDM, HOMA-IR was significantly higher (P<0.001). Interpretation and conclusion This study highlights significant associations between GCKR and GLIS3 polymorphisms and the risk of GDM in South Indian women, supporting the role of ethnicity-specific genetic screening in predicting GDM risk.