Despite advancement in cancer treatment, oral cancer has a poor prognosis and is often detected at late stage. To overcome these challenges, investigators should search for early diagnostic and prognostic biomarkers. More than 700 bacterial species reside in the oral cavity. The oral microbiome population varies by saliva and different habitats of oral cavity. Tobacco, alcohol, and betel nut, which are causative factors of oral cancer, may alter the oral microbiome composition. Both pathogenic and commensal strains of bacteria have significantly contributed to oral cancer. Numerous bacterial species in the oral cavity are involved in chronic inflammation that lead to development of oral carcinogenesis. Bacterial products and its metabolic by-products may induce permanent genetic alterations in epithelial cells of the host that drive proliferation and/or survival of epithelial cells. Porphyromonas gingivalis and Fusobacterium nucleatum induce production of inflammatory cytokines, cell proliferation, and inhibition of apoptosis, cellular invasion, and migration thorough host cell genomic alterations. Recent advancement in metagenomic technologies may be useful in identifying oral cancer-related microbiome, their genomes, virulence properties, and their interaction with host immunity. It is very important to address which bacterial species is responsible for driving oral carcinogenesis. Alteration in the oral commensal microbial communities have potential application as a diagnostic tool to predict oral squamous cell carcinoma. Clinicians should be aware that the protective properties of the resident microflora are beneficial to define treatment strategies. To develop highly precise and effective therapeutic approaches, identification of specific oral microbiomes may be required. In this review, we narrate the role of microbiome in the progression of oral cancer and its role as an early diagnostic and prognostic biomarker for oral cancer.