Inflammatory reactions and oxidative stress play a major role in cancer expansion. Boeravinone B (BB) had already proofed their anti-inflammatory and antioxidant effects against various animal models of disease. In this experimental research, the chemoprotective effect of BB against skin cancer caused by 7,12-dimethylbenz(a)anthracene (DMBA)/croton oil was investigated and the possible mechanism was explored. Swiss albino mice were used in the current protocol. 100 µg/100 mL acetone, DMBA was used for induction the skin cancer and, after the 2-week repeated dose of croton oil (1% in acetone) give to the mice till end of the protocol. The mice were received the oral dose of BB (1.25, 2.5 and 5 mg/kg, body weight). The body weight and tumor incidence were estimated at regular time interval. At the end of the protocol, the antioxidant, phase I, phase II, pro-inflammatory cytokines and inflammatory mediators were scrutinized. The mRNA expression of pro-inflammatory cytokines and inflammatory mediators were estimated. BB treatment significantly (p < 0.001) reduced tumor incidence, tumor yield, average latency period and tumor burden in a dose-dependent manner. BB treatment considerably (p < 0.001) reduced the levels of lipid peroxidation (LPO) and increased the level of superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GPx), catalase (CAT) in DMBA/croton-induced skin cancer. BB treatment significantly (p < 0.001) reduced the level of phase I and phase II enzymes. BB treatment considerably reduced the cytokines include tumor necrosis factor-α (TNF-α), interleukin-18 (IL-18), interleukin-1β (IL-1β), interleukin-6 (IL-6) and inflammatory parameters such as transforming growth factor beta 1 (TGF-β1), prostaglandin E2 (PGE₂), nuclear kappa B factor (NF-κB) and cycloxgenase-2 (COX-2) in DMBA/croton-induced skin cancer mice. BB considerably (p < 0.001) reduced the mRNA expression of pro-inflammatory cytokines and inflammatory mediators. The results of the current investigation suggest that oral administration of boeravinone B significantly reduced skin cancer in mice via reduction of inflammatory reaction.