Baicalein, one of the four major flavanoids extracted from the root of Scutellaria baicalensis, has been shown to exert chemopreventive effect against several cancers, including skin cancer. However, the precise mechanisms remain to be elucidated. In the present study, we investigated the chemopreventive activity of baicalein against 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-mediated skin tumorigenesis in C57BL/6 mice. We found that topical treatment with baicalein resulted in a significant inhibitory effect on DMBA/TPA-mediated tumor promotion. Furthermore, we observed that baicalein suppressed cell proliferation and promoted apoptosis in DMBA/TPA-mediated group. Additionally, pretreatment with baicalein inhibited the production of inflammatory cells in DMBA/TPA-induced skin/tumors. Further experiments showed that baicalein reduced TPA-induced skin hyperplasia as well as infiltration of polymorphonuclear leukocytes in the dermis. In conclusion, our data suggest that baicalein inhibits DMBA/TPA-induced skin tumorigenesis by suppressing proliferation and inflammation and promoting apoptosis.