Plumbago zeylanica, commonly known as white leadwort, found abundantly in the plains of Bengal and southern India, was tested for its possible in vivo protective effect against cyclophosphamide-induced genotoxicity and oxidative stress in Swiss albino mice. Pretreatment with the alcoholic root extract of Plumbago zeylanica (250 and 500 mg/kg body weight orally for 5 days) significantly reduced the frequency of micronucleated polychromatic erythrocytes (MnPCEs), increased the PCE/NCE (normochromatic erythrocyte) ratio in the bone marrow, and decreased the levels of lipid peroxidation products with concomitant changes in the status of antioxidants. Both doses of Plumbago zeylanica were effective in exerting a protective effect against cyclophosphamide-induced genotoxicity and oxidative stress.