Epigenetic, genetic predisposition and epidemiological risk factors were suggested to be involved in the carcinogenesis of oral cancer. In this study, we focused on the associations of MET single-nucleotide polymorphisms (SNPs) to oral cancer susceptibility and clinicopathological characteristics. The MET SNPs rs41736, rs41739, rs1621, and rs33917957 in 1198 controls and 1318 male patients with oral cancer were analyzed with real-time polymerase chain reaction. Our results revealed that the cigarette smokers among the oral cancer patients who carried the rs1621 polymorphic variant "G" were significantly associated with lower risk to develop oral cancer [OR (95% CI) = 0.463 (0.226-0.948)]. The male oral cancer patients who with the genotypic variant "G" of rs33917957 were associated with lower risk of cell differentiated grade (p = 0.041). In the TCGA database, the MET expressions were upregulated in oral cancer tissues compared to normal tissues, and were correlated with poor cell differentiated and poorer prognoses in smoker groups. In conclusion, these novel findings underscore the role of MET genetic variants in oral cancer susceptibility, particularly in smokers, and highlight the potential of these variants for prognosis and disease prediction.