Introduction: The study indicated that XPD and XPG gene polymorphism is associated with the development of oral potentially malignant disorders (OPMDs) and oral squamous cell carcinoma. Xeroderma pigmentosa (XP) is a part of the complex DNA repair system. Xeroderma pigmentosum group G (XPG) and xeroderma pigmentosum group D (XPD) gene function in the nucleotide excision repair (NER) pathway. XPG and/or XPD gene alterations can cause defective DNA repair efficiency which ultimately leads to genomic instability and carcinogenesis. Thus, this study helps in early detection of OPMDs among individuals who have not yet developed any oral lesions and also helps in the management of oral squamous cell carcinoma as if XP gene polymorphism is known. Aims and Objectives: The aim of the study was to evaluate the expression of XPD and XPG gene polymorphism in oral squamous cell carcinoma cases. The study also had the objective to evaluate and compare the expression of XPG and XPD gene polymorphism in oral squamous cell carcinoma (OSCC) cases, tobacco chewers without any oral lesions, and normal healthy individuals without any habit. Materials and Method: A total of 150 subjects were included in the study and genotyped for the expression of XPD (AC) and XPG (GC) gene polymorphism using polymerase chain reaction (PCR) and agarose gel electrophoresis method. Results: XPD genotype for the study shows that most of the cases of OSCC show heterozygous (AC) genotype (64%), whereas in tobacco chewers without any oral lesions wild (AA) genotype (54%) is more common than other types. XPG genotype for the study shows that wild (GG) type is the most dominant genotype both in OSCC cases (78%) and tobacco chewers without any oral lesion (56%). Conclusion: The study shows the association of XPD and XPG gene polymorphism with the risk of developing OPMDs and oral cancer.