2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside (THSG) has been shown to have antioxidative and anti-inflammatory effects. Oxidative and inflammatory reactions are related to the development of colorectal carcinoma (CRC). In the present study, we characterized the preventive activities of THSG on colon carcinogenesis using the azoxymethane- (AOM-) mediated rat colon carcinogenesis model. F344 male rats were randomly divided into 5 groups (untreated and AOM model rats treated with or without THSG at 30, 150, or 250 mg/kg) after which the numbers of aberrant crypt foci (ACF) were assessed in the colon tissues of all rats. The expressions of nuclear factor-κB (NF-κB), cyclooxygenase-2 (COX-2), matrix metalloproteinase proteins (MMPs), and carcinoembryonic antigen (CEA) were measured as effective early predictors of CRC using western blot analysis. Treatment with THSG (150 or 250 mg/kg) induced a 50% reduction in total colonic ACF formation (P < 0.05). Furthermore, our results revealed a downregulation of CEA and NF-κB protein levels in the reduced number of ACF elicited by treatment with THSG, whereas levels of COX-2 and MMPs proteins were not changed. Collectively, THSG may be a promising natural lead compound or drug candidate for treating early phases of CRC.