Saraca asoca (Family Caesalpiniaceae) has been widely used in traditional Indian medicine especially due to its wound-healing property. The present study investigates the chemopreventive property of flavonoids from Saraca asoca (flowers) on 2-stage skin carcinogenesis in mice models. Skin cancer was induced in Swiss albino mice by single topical application of 7,12-dimethyl benzanthracene (100 µg/50 µL of acetone) followed by thrice a week treatment of croton oil for 20 weeks. The topical pretreatment of the flavonoid fraction from S asoca (FF S asoca) was 30 minutes prior to the application of croton oil thrice weekly for 20 weeks. At the end of the experimental period the animals were sacrificed, and the tumor statistics and various marker parameters were studied (enzyme assays, Western blotting). The pretreatment of the FF of S asoca caused significant reduction in the number of tumors per mouse and the percentage of tumor-bearing mice. Also, the latency period for the appearance of the first tumor was delayed by S asoca pretreatment. In plant-treated animals there was a significant increase in the levels of reduced glutathione, catalase, and protein in skin when compared with the untreated animals. Conversely, there was a significant decrease in the lipid peroxidation levels. A significant reduction in the expression of ornithine decarboxylase, a key enzyme in the promotion stage of 2-stage skin cancer, in the plant-treated group was also observed. These findings suggest the chemopreventive activity of flavonoids from S asoca on 2-stage skin carcinogenesis.