Doxorubicin (DOX) is one of the most potent antitumor agents, but its use is limited by development of cardiotoxicity involving cardiomyocyte apoptosis and myocardial fibrosis. This study was aimed to evaluate the cardio- protective effects of carvedilol and N-acetylcysteine alone and in combination on doxorubicin-induced cardiotoxicity in rats. Male albino rats were classified into 7 equal groups; 1st group which is normal control group, 2nd and 3rd group involve normal rats receive carvedilol (10 mg/kg/day) and N-acetylcysteine (200 mg/kg/day) respectively. Cardiotoxicity was induced by I.P injection of 6 equal doses of doxorubicin (2.5 mg/kg) within two weeks. Cardio-toxic rats were divided into 4 groups; DOX untreated group, carvedilol treated group, N-acetylcysteine treated group and (carvedilol + N-acetylcysteine) treated group. The drugs were given for 14 day concomitantly with I.P doxorubicin administration. The current work revealed that treatment with either carvedilol or/and N-acetylcysteine resulted in a significant improvement of doxorubicin-induced cardiotoxicity; evident by a significant reduction of heart rate, ST segment elevation, serum creatinine phosphokinase (CPK-MB), troponin-I activity, serum interluken-6 (IL-6),cardiac malondialdehyde (MDA) , significant elevation of reduced glutathione (GSH) and serum SIRT 1 gene expression . Both drugs showed significant improvement of electrophysiological and biochemical parameters which were confirmed with histopathological examination with more significant effect of combination therapy over the effect of each drug alone.