Irinotecan (CPT-11), commonly used in the treatment of many cancer types, may have several side effects that limit the use of CPT-11 in specific tissues such as the heart. In the current study, positive effects of curcumin (CRC) was determined in terms of antioxidant and anti-inflammatory properties against heart damage, caused by CPT-11, in rats. Rats were divided randomly into four equal groups (Control, CPT-11, CRC, and CPT-11 + CRC). CPT-11 10 mg/kg/day was administered intraperitoneally and CRC 100 mg/kg(-1) was given orally. Blood and tissue samples were collected from all groups at day 30 for the detection of oxidative stress, histological changes, and cytokine levels. Results showed that CPT-11 caused dramatic changes in heart tissue for oxidative stress parameters (TBARS, SOD, CAT, GSH, and GPx levels), histological tissue damage, and cytokine levels (TNF and IL-4). CRC therapy reversed the elevated oxidative stress, histological tissue damages, and immunological changes and protected cardiac tissue against CPT-11 toxicity when given together with CPT-11.