This study aims to evaluate the potential benefits and challenges of integrating oral microbiome research into the clinical management of oral potentially malignant disorders (OPMD) and oral squamous cell carcinoma (OSCC). The oral microbiome has gained significant attention for its role in the pathogenesis and progression of these conditions, with emerging evidence suggesting its value as a diagnostic and prognostic tool. By critically analyzing current evidence and methodological considerations, this manuscript examines whether microbiome analysis in biopsy samples can aid in the early detection, prognosis, and management of OPMD and OSCC. The complexity and dynamic nature of the oral microbiome require a multifaceted approach to fully understand its clinical utility. Based on this review, we conclude that studying the oral microbiome in this context holds significant promise but also faces notable challenges, including methodological variability and the need for standardization. Ultimately, this manuscript addresses the question, “Should such research be undertaken, given the intricate interactions of various factors and the inherent obstacles involved?”, and also emphasizes the importance of further research to optimize clinical applications and improve patient outcomes.