Oral potentially malignant disorders (OPMD) and oral squamous cell carcinoma (OSCC) represent a significant global health burden due to their potential for malignant transformation and the challenges associated with their diagnosis and treatment. Chemoprevention, an innovative approach aimed at halting or reversing the neoplastic process before full malignancy, has emerged as a promising avenue for mitigating the impact of OPMD and OSCC. The pivotal role of chemopreventive strategies is underscored by the need for effective interventions that go beyond traditional therapies. In this regard, chemopreventive agents offer a unique opportunity to intercept disease progression by targeting the molecular pathways implicated in carcinogenesis. Natural compounds, such as curcumin, green tea polyphenols, and resveratrol, exhibit anti-inflammatory, antioxidant, and anti-cancer properties that could make them potential candidates for curtailing the transformation of OPMD to OSCC. Moreover, targeted therapies directed at specific molecular alterations hold promise in disrupting the signaling cascades driving OSCC growth. Immunomodulatory agents, like immune checkpoint inhibitors, are gaining attention for their potential to harness the body’s immune response against early malignancies, thus impeding OSCC advancement. Additionally, nutritional interventions and topical formulations of chemopreventive agents offer localized strategies for preventing carcinogenesis in the oral cavity. The challenge lies in optimizing these strategies for efficacy, safety, and patient compliance. This review presents an up to date on the dynamic interplay between molecular insights, clinical interventions, and the broader goal of reducing the burden of oral malignancies. As research progresses, the synergy between early diagnosis, non-invasive biomarker identification, and chemopreventive therapy is poised to reshape the landscape of OPMD and OSCC management, offering a glimpse of a future where these diseases are no longer insurmountable challenges but rather preventable and manageable conditions.