<p>This review critically examines the intricate and dynamic interactions between the oral microbiome and oral squamous cell carcinoma (OSCC), highlighting the growing recognition of the microbiome’s role in the onset, progression, and potential treatment of this malignancy. Accumulating evidence suggests that dysbiosis within the oral microbial community can promote carcinogenesis through mechanisms such as chronic inflammation, genotoxic effects, and immune modulation. In contrast, certain commensal bacteria may exert protective influences, underscoring the complexity of host–microbe relationships in the oral environment. Traditional OSCC treatments such as surgery, radiation, and chemotherapy, while standard, often fall short in improving long-term outcomes and minimizing side effects. In this context, microbiome-based strategies offer promising avenues for early diagnosis, risk prediction, and personalized therapy. Recent breakthroughs in microbial genome analysis, particularly next-generation and single-cell sequencing, have enabled high-resolution profiling of oral microbial communities, uncovering functional and taxonomic patterns linked to OSCC. By bridging microbiology and oncology, this review underscores the potential of microbial biomarkers and therapeutic targets in improving clinical management and outcomes in OSCC. </p>