The aim of this study was to assess the efficiency of grape seed extract (GSE) against doxorubicin (DOXO)-induced cardiotoxicity in adult male albino rats, monitored by histological, immunohistochemical and electron microscopical methods. Methods: Thirty adult male albino rats were included in this study. They were divided into four groups: Group I (control group) included 9 rats .Group II (GSE treated group): 7rats were given 100mg/kg GSE dissolved in 0.5 ml distilled water orally for 12 days. Group III (DOXO treated group): 7rats were injected intraperitonial with 20mg/kg DOXO on day 7 from the start of the experiment. Group IV (GSE and DOXO treated group): 7rats were given GSE as in Group II for 12days and on the 7th day, a single dose of DOXO was injected with the same dose and route as in Group III. All rats were sacrificed on day 13. Myocardial sections were stained with H&E, Masson’s trichrome and immunohistochemical stain for Bcl-2. The mean area percent of collagen fibers and immunoreactivity of Bcl-2 were measured. Other myocardial specimens were prepared for electron microscopic examination.Results: Group I and II revealed similar histological architecture of the myocardium on light and electron microscopic examination and a non significant difference in the mean area % of collagen fibers and Bcl-2 immunoreaction. Group III myocardial sections stained with H&E revealed disorganized, disrupted and degenerated cardiac muscle fibers that exhibited homogenous acidophilic sarcoplasm with loss of cross striations, sarcoplasmic vacculations, pyknotic nuclei with congested, dilated blood capillaries, RBCs extravasations, fibroblast proliferation and inflammatory cellular infiltration inbetween. The mean area % of collagen fibers showed a significant increase and the mean area % of Bcl-2 immunoreaction showed a significant decrease compared to Group I and II. Ultrastructural examination of Group III revealed myofibrillar loss, karyorrhexis and fragmented mitochondria. Mitochondrial membrane constriction (fission) was observed more common than mitochondrial membrane contact sites (fusion). Group IV showed by light and electron microscopic examination attenuation of histological alternations in the myocardium caused by DOXO in Group III. There was a significant decrease in the mean area % of collagen fibers and a significant increase in the mean area % of Bcl-2 immunoreaction compared to Group III. Conclusion: Treatment with GSE before and combined with DOXO attenuated the DOXO induced cardiotoxicity.