Cadmium is an environmental metal toxin implicated in human diseases. Mangiferin (MGN), a naturally occurring glucosylxanthone, is present in Mangifera indica. In this study, the protective role of MGN against cadmium chloride (CdCl2)-induced genotoxicity was studied in Swiss albino mice. Mice were administered with single intra-peritoneal (i.p.) optimal dose of MGN (2.5 mg/kg b.wt.) before treatment with various concentrations of CdCl2 (7, 8, 9, 10 and 11 mg/kg b.wt.). The LD 50(30) was found to be 8.5 mg/kg b.wt. for DDW + CdCl2 group, while it was increased to 9.77 mg/kg after MGN treatment resulting in increase in the LD50(30) value by 1.26 mg, with a dose reduction factor (DRF) of 1.14. Treatment of mice to various doses of CdCl2 resulted in a dose-dependent increase in the frequency of micronucleated polychromatic (MnPCE) and normochromatic erythrocytes (MnNCE), with corresponding decrease in the polychromatic / normochromatic erythrocyte ratio (PCE/NCE ratio) at various post-treatment times. MGN (2.5 mg/kg b.wt.) pretreatment significantly (p < .001) reduced the frequency of MnPCE, MnNCE and increased PCE/NCE ratio when compared with the DDW + CdCl2 group at all post-treatment times indicating its antigenotoxic effect. Further, pretreatment of MGN declined the lipid peroxidation (LPx) content in liver, whereas significant increase was observed in hepatic Glutathione (GSH), glutathione-S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT) activity. Our study revealed that MGN has potent antigenotoxic effect against CdCl2-induced toxicity in mice, which may be due to the scavenging of free radicals and increased antioxidant status.