Head and neck squamous cell carcinoma (HNSCC) is one of the leading health issues globally. Oral cavity harbors a rich variety of microbes, which are in charge of preserving homeostasis under healthy circumstances. Imbalance among this microbial community—is referred to as oral dysbiosis—that has the potential to cause oncogenesis by chronic inflammation, immune modulation, and genotoxic effect. Pathogenic bacteria, including Porphyromonas gingivalis, Fusobacterium nucleatum and Treponema denticola have been linked with the development & progression of tumors. Dysbiotic microenvironment is capable of causing DNA damage, inducing epithelial-mesenchymal transition, and remodeling the tumor microenvironment, hence facilitating cancer development and progression. The current review aims at tackling the multifaceted relationship between oral dysbiosis and head and neck squamous cell carcinoma (HNSCC) in light of underlying molecular mechanisms, potential diagnostic application and therapeutic measures.