Background: In this study, we investigated the chemopreventive efficacy of fucoxanthin (Fx) on 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral cancer in hamsters. Materials and Methods: Twenty-four male Syrian golden hamsters were randomly allotted to four groups with six hamsters each. Squamous cell carcinogenesis was initiated by administering 0.5% DMBA in the left oral mucosa of hamsters for 10 weeks. The complete formation of oral tumor (OT) was confirmed via hematoxylin and eosin staining and biochemical analysis, as well as via molecular markers using plasma samples and in buccal and liver tissue samples. Results: Significant increase in the level of antioxidant, lipid peroxides (LPOs), and liver marker enzymes was observed in control animals. Increased rate of cell proliferation and decreased expression of apoptotic proteins were observed in buccal tumor in control animals. Treatment of DMBA-induced animals with Fx (50 mg/kg body weight) resulted in mild-to-moderate premalignant lesions, such as hyperplasia and dysplasia, but control animals showed the development of OT. Furthermore, the levels of LPO, antioxidants, and xenobiotic agents were altered due to Fx-administered DMBA-induced hamster showed reduced expression pattern of proliferating cell nuclear antigen and moderate expression pattern of caspases-9 and 3 and p53 were observations. Conclusion: In this study, the chemoprotective potential of Fx was due to the antiproliferative, antiapoptotic, and antioxidant effects of Fx, as well as due to anti-LPO effects in the DMBA-induced hamster cheek pouch carcinogenesis.