Medicinal plants, especially rich in polyphenolic compounds, have been suggested to be chemopreventive on account of antioxidative properties. Salvia officinalis L., an aromatic and medicinal plant, is widely used in folk medicine and is well known for its antioxidant properties. Therefore, the present study was designed to investigate the antioxidative, possible genotoxic, and antigenotoxic potency of S. officinalis extract against cyclophosphamide (CYP)-induced oxidative stress and genotoxicity in Wistar albino rats. Animals were orally dosed with S. officinalis extract (50, 100, and 150 mg/kg body weight) for 7 days before the administration of a single intraperitoneal dose of CYP (40 mg/kg body weight). The biochemical and cytogenetic determinations were carried out 24 h aft er CYP injection. The activities of malondialdehyde, superoxide dismutase, and catalase were determined in liver, kidney, and heart tissues. The frequency of micronucleated polychromatic erythrocytes (MNPCEs) and the ratio of polychromatic erythrocytes to normochromatic erythrocytes (PCE/NCE) were also evaluated. Additionally, the antioxidant capacity of the extract was analyzed. The micronucleus assay revealed that all doses of the extract tested presented no genotoxic activity; in addition, the 2 highest doses reduced the MNPCEs and increased the PCE/NCE ratio in the bone marrow and restored the oxidative stress markers in CYP-treated rats. In correlation with these findings, S. officinalis extract exhibited high antioxidant capacity. The results of the present study suggest that the methanolic extract of S. officinalis has a protective effect against CYP-induced oxidative stress and genotoxicity through its antioxidant property.