Type 2 diabetes mellitus (T2DM) susceptibility has increased due to the independent risks of genetic polymorphism and obesity as well as combinations of these. Despite recent advancements in T2DM management and diagnosis, the challenges of susceptibility and prognosis still remain. The present work is attempted to understand the association of methylenetetrahydrofolate reductase (MTHFR) (rs1801133) and FTO (rs9939609) genetic polymorphisms and obesity with T2DM among the Bengalee Hindu caste population of West Bengal, India. One hundred and four clinically diagnosed T2DM male patients and 176 healthy males, without family history of T2DM, (control group) of the endogamous linguistic group (Bengalee Hindu caste) participated. Genotyping was performed using the PCR-RFLP method following the isolation of genomic DNA. MTHFR (rs1801133) genetic polymorphism with CT genotype revealed significantly higher risk (OR = 3.44; p = .01) of T2DM compared to the CC genotype. The attenuation of MTHFR-T2DM risk after adjustment for age and waist circumference revealed obesity and age effects in progression of T2DM. T2DM patients also had significantly (p < .05) higher overall obesity, central obesity, and SBP compared to the controls. However, FTO (rs9939609) genetic polymorphism demonstrated no significant (p= .854) effect on T2DM and obesity. The present study identified that MTHFR genetic polymorphism and obesity might be used as screening tools for early prognosis of T2DM. © 2021 Informa UK Limited, trading as Taylor & Francis Group.