Cancer chemoprevention is a novel and recognized approach to inhibit, delay or reverse the process of cancer development by using natural products. Our aim of this study was to examine the chemopreventive potential of fish oil on 7, 12-Dimethylbenz (a) Anthracene (DMBA)-initiated and croton oil-promoted skin papillomagenesis model in mice. Oral treatment of fish oil at a dose of 25 μl per animal resulted in significant reduction of tumor incidence, tumor burden, tumor yield, and the cumulative number of papillomas in DMBA+croton oil+fish oil treated group compared to only DMBA +croton oil administered positive control group. Pre-treatment of fish oil also increased the latency period of tumor development and a significant reduction in the weight and size of the skin papillomas. Furthermore, biochemical assays revealed a significant increase in the hepatic enzymatic and nonenzymatic antioxidants like glutathione-S-transferase, superoxide dismutase, catalase, and reduced glutathione whereas lipid peroxidation was found to be significantly reduced as a result of fish oil treatment. Thus, the results of the present study clearly indicate that fish oil has potent chemopreventive efficacy against two-stage skin carcinogenesis which can be partially attributed to its anti-oxidative and anti-peroxidative effect.