Introduction: The stress-oxidative is involved in doxorubicin (DOX)-induced cardiotoxicity. Due to the potential and previous reported for antioxidant properties of atorvastatin, omega-3, vitamin E and vitamin C, their efficacy to prevention of DOX-induced cardiotoxicity was investigated in this study. Methods: Fifty-six male rats were divided into 8 groups which received omega-3, atorvastatin, vitamin E, vitamin C, normal saline and dimethyl sulfoxide (DMSO) via gavage for 14 days then a single dose of DOX (20 mg/kg) was injected intraperitoneally except two last groups that received only normal saline or DMSO. The level of oxidative stress parameters like ferric reducing ability of plasma (FRAP) before and after DOX injection and malondialdehyde (MDA) of heart were estimated. Also the histopathologic assessments were done on heart sample at the end of experimental period. Results: The results showed that compared to other agents, omega-3 could emerge as the most protection against DOX. Its pretreatment led to one of the most FRAP changing percent meanwhile less MDA value and cardio pathologic indexes almost close to control groups compared to that of other agents (P<0.01). Conclusion: Omega-3 may have a promising protective effect against DOX-induced cardio toxicity.