Zingerone (ZO), a dietary phenolic compound was investigated for its ability to protect against radiation-induced oxidative stress and DNA damage in Chinese hamster fibroblast cells (V79). Cells treated with optimal dose of ZO (25 μg/ml), 1 h prior radiation exposure resulted in a significant (P<0.01) elevation of cell survival and decreased the genotoxicity (micronuclei and comet assays). Further, pretreatment with ZO significantly reduced radiation-induced oxidative stress as indicated by decreased reactive oxygen species levels and inhibition of mitochondrial depolarisation. The experiments conducted to evaluate the intracellular antioxidant activity in ZO-pretreated cells demonstrated a significant (P<0.01) increase in the various antioxidants like glutathione, gluthione-S-transferase, superoxide dismutase, catalase and a significant (P<0.01) decrease in malondialdehyde levels versus irradiation alone. Further, ZO scavenged various free radicals generated in vitro (OH·, O(2)·, DPPH·, ABTS·(+) and NO·) in a dose-dependent manner. The anti-apoptotic effect of ZO pretreatment was by the inhibition of the activation of capase-3, by upregulating Bcl-2 and down-regulating Bax proteins. Our study demonstrates the antagonistic effect of ZO against radiation-induced cytotoxicity. Further, ZO rendered anti-genotoxic, anti-apoptotic and anti-lipid peroxidative potency, plausibly ascribable to its antioxidant/free radical scavenging ability and also by the suppression of radiation-induced oxidative stress.