Adriamycin (ADR) efficacy in cancer chemotherapy is well-established. However, ADR-induced cardiotoxicity remains a significant challenge. Aged garlic extract (AGE) is a natural polyphenol with high antioxidant potential. This study was planned to determine the cytoprotective and antioxidant actions of AGE against the cardiotoxic effect of ADR in rats. Six equal groups, control, ADR-treated (single dose of 10 mg/kg on day 8); AGE-treated (one dose of 250 mg/kg for 14 days); AGE plus ADR-treated (one dose of 250 mg/kg AGE for one week plus ADR injection of 10 mg/kg on day 8); ADR plus AGE-treated (single ADR injection of 10 mg/kg on day 8 plus AGE of 250 mg/kg once from 8th to 14th day); combined AGE plus ADR plus AGE-treated (one dose of 250 mg/kg AGE for 14 days plus single ADR injection of 10 mg/kg on day 8). Sera and cardiac samples were collected on day 15 and prepared for histological, ultrastructural and biochemical study. Disorganization, focal degeneration and necrosis with apoptotic changes of the cardiac myofibrils were observed in ADR-treated rats. Also, reduction in level of total creatine kinase, lactic dehydrogenase, alkaline phosphatase enzymes, glutathione, glutathione- peroxidase, superoxide dismutase, and catalase activities and elevation in malondialdehyde concentration were detected in ADR-treated rats. However, combination of AGE attenuated most of the histopathological, ultrastructural, and biochemical changes induced by ADR. Combination of AGE attenuated the cardiotoxic effects-induced by ADR through its antioxidant and cytoprotective potentials. Therefore, AGE can use as adjunct during administration of ADR in cancer therapy.