In this study, the protective role of grape seed extract (GSE) against doxorubicin (DOX)-induced cardiotoxicity and genotoxicity has been evaluated in male Mus musculus var. albino mice. The micronucleus (MN) test in erythrocytes and the chromosome aberration (CA) test in bone marrow cells were used. Also, levels of reduced glutathione (GSH) and lipid peroxidation as malondialdehyde (MDA) in heart homogenates were measured, and in addition the changes in heart histology were investigated. The mice were randomly divided into six groups. Group I (negative control) received intraperitoneal injections of isotonic saline (0.02 mL/g) for 6 consecutive days, Group II received intraperitoneal injections of DOX (2.5 mg/kg of body weight, six doses every other day; cumulative dosage, 15 mg/kg of body weight) for 6 consecutive days, Group III received GSE (50 mg/kg of body weight, 21 doses every other day; cumulative dosage, 1,050 mg/kg of body weight) for 21 consecutive days, Group IV received GSE (150 mg/kg of body weight, 21 doses every other day; cumulative dosage, 3,150 mg/kg of body weight) for 21 consecutive days, Group V received GSE (50 mg/kg of body weight, 28 doses every other day; cumulative dosage, 1,400 mg/kg of body weight) for 28 consecutive days plus DOX (2.5 mg/kg of body weight, six doses every other day; cumulative dosage, 15 mg/kg of body weight) for 6 consecutive days, and Group VI received GSE (150 mg/kg of body weight, 28 doses every other day; cumulative dosage, 4,200 mg/kg of body weight) for 28 consecutive days plus DOX (2.5 mg/kg of body weight, six doses every other day; cumulative dosage, 15 mg/kg of body weight) for 6 consecutive days. DOX induced heart damage as indicated from a pronounced change in heart histology. In the DOX-treated group, there was a significant increase in MDA content in the heart homogenate, and the level of GSH was significantly decreased. DOX induced genotoxicity by increasing the number of aberrant metaphases (AMNs), MNs, and structural chromosomal aberrations (CAs) such as chromatid breaks, dicentrics, acentric fragments, and gaps and showed a detractive effect on the mitotic index (MI) of cells. Pretreatment with GSE before treatment with DOX significantly protected the heart tissue by ameliorating its antioxidant activity. In Groups V and VI, the MDA level of heart tissue was significantly decreased, and the GSH level was increased compared to the DOX-treated group. Moreover, GSE significantly protected bone marrow chromosomes from DOX-induced genotoxicity by reducing the total AMNs and the frequency of structural CAs. GSE treatment also decreased the frequency of MNs and increased the MI values. It could be concluded that GSE acts as a potent antioxidant to prevent heart damage and genotoxicity of bone marrow cells. © Mary Ann Liebert, Inc.