Background: Oral potentially malignant disorders (OPMD) of the oral mucosa are one of the increased risks of oral cancer transformation. This is primarily caused by habitual risk factors such as tobacco (smoking and smokeless), betel quid chewing and alcohol consumption, which are the most important etiologic factors. Multiple studies have assessed the correlation of increased oral cancer and oral potentially malignant disorder with polymorphism in DNA repair genes. Highlight: This review explores the genetic perspectives of the OPMD with special emphasis on DNA repair genes polymorphism associated with the risk exposures. The base Excision Repair (BER) pathway plays an important role in repairing damaged base pairs caused by oxidative stress due to tobacco carcinogens. Adenosine diphosphate ribosyl transferase (ADPRT), x-ray repair cross-complementing 1 (XRCC1), and apurinic/apyimidinic endonuclease (APE1), MGMT and other repair gene polymorphisms are involved with OPMD associated with habitual risk factors. Conclusion: Genetic differences between various ethnicities and differences in the carcinogenesis of OPMD development in various countries could partially explain the discrepant of these gene-environmental lifestyle habits. An understanding of DNA repair genetic variants associated with habitual risk factors contribute to more accurate identification and establishing tailor-made prevention measures.