The main aim of the current study was to determine cardio-toxicity mechanisms of H. lepturus and protective effect of curcumin against this toxin in rats, using isolated heart mitochondria and cardiomyocytes. Our findings indicated that H. lepturus venom caused significantly ((P<0.05) cytotoxicity and caspase 3 activation in cardiomyocytes and mitochondrial dysfunction including increased mitochondrial ROS level, swelling in the mitochondria, decline in the mitochondria membrane potential (MMP), decrease in the cytochrome-c oxidase activity (complex IV), decrease ATP level and finally mitochondrial outer membrane (MOM) rupture in isolated mitochondria. Our results showed that the administration of curcumin efficiently decreased (P<0.05) cytotoxicity and caspase 3 activation, ROS formation, MMP collapse, mitochondrial swelling and mitochondrial outer membrane (MOM) rupture. Our findings suggest H. lepturus venom cusses a disruptive effect on mitochondrial respiratory chain, especially on complex II, and IV that predispose cardiomyocytes to ATP depletion and death signaling that could be protected with administration of curcumin.