INTRODUCTION AND AIMS: This study aimed to examine the causal link between oral microbiome and the risk of oral and oropharyngeal squamous cell carcinoma (OOPSCC) using Mendelian randomization (MR). METHODS: Utilizing single nucleotide polymorphisms as instrumental variables, we applied the MR inverse-variance weighted approach to assess the impact of salivary and tongue microbiome on OOPSCC. The data were obtained from the CNGBdb database and the UK Biobank, and analytical procedures were performed using the R package 'TwoSampleMR'. To ensure the robustness of our findings, we conducted sensitivity studies, which included the MR-Egger intercept test, to establish strong correlations and eliminate the phenomenon of horizontal pleiotropy. RESULT: Our large-scale MR study revealed a genetically predisposed causal relationship between 13 microbial taxa, each from saliva and tongue, with OOPSCC. Notably, microbial taxa from six genera, including Prevotella, Neisseria, Veillonella, Granulicatella, Treponema, and Streptococcus, in both salivary and tongue microbiomes, showed this relationship. Conversely, several taxa, including Hemophilus, Solobacterium, Campylobacter, and Porphyromonas, predominantly demonstrated an inverse relationship, suggesting a protective effect. The robustness of our findings was further confirmed through sensitivity analyses, providing additional confidence in our results. CONCLUSION: Our MR study indicates that the oral microbiota has a significant causal impact on the risk of oral and oropharyngeal cancers. The microbial biomarkers we identified, which are linked to OOPSCC, have the potential to uncover the underlying mechanisms and pave the way for new therapeutic approaches for targeted treatment of these malignancies.