Arsenic trioxide (As2O3) is utilized for treating patients suffering from hematological malignancies particularly acute promyelocytic leukemia. Unfortunately, the extensive application of this chemotherapeutic agent has been limited due to its adverse effects such as cardiotoxicity. Ellagic acid, as a phenolic compound, has shown to exert antioxidant, anti-inflammatory, antifibrotic, and antiatherogenic properties. It is also capable of protecting against drug toxicity. In this study, we evaluated whether ellagic acid can protect against As2O3-induced heart injury in rats. Thirty-two male Wistar rats were randomly divided into four treatment groups, that is, control (0.2 mL of normal saline, intraperitoneally (ip)), As2O3 (5 mg/kg, ip), As2O3 plus ellagic acid, and ellagic acid (30 mg/kg, orally) groups. The drugs were administered daily for 10 days and pretreatment with ellagic acid was performed 1 h prior to As2O3 injection. Cardiotoxicity was characterized by electrocardiological, biochemical, and histopathological evaluations. Our results showed that ellagic acid pretreatment significantly ameliorated As2O3-induced increase in glutathione peroxidase activity and malondialdehyde concentration (p < 0.05 and p < 0.001, respectively) and also diminished QTc prolongation (p < 0.0001) and cardiac tissue damages. Pretreatment with ellagic acid also lowered the increased troponin I (p < 0.0001) and creatine kinase isoenzyme MB (p < 0.01) levels in response to As2O3. In conclusion, results of this study demonstrated that ellagic acid has beneficial cardioprotective effects against As2O3 toxicity. It is suggested that the protective effects were mediated by antioxidant properties of ellagic acid.