Abstract: Background and Objective: Arnebia hispidissima (F. Boraginaceae) has been found to have cardiac and febrifuge properties. It has long been used in traditional system of medicine for the treatment of heart ailments, headache and fever. This study aimed to investigate the protective effect of Arnebia hispidissima extract (AHE) on carbon tetrachloride (CCl4)-induced cardiotoxicity and nephrotoxicity. Materials and Methods: Adult rats were divided into five groups and medicated as follows: (1) The control group received the vehicles (olive oil; 1 mL kg–1, i.p.+3% Tween 80; 1 mL kg–1, p.o.). (2) CCl4 group of animals was administered with 20% CCl4 in olive oil (1 mL kg–1, p.o.). (3) Silymarin group was co-administered with CCl4 plus silymarin (50 mg kg–1, p.o.). (4) CCl4 plus AHE (200 mg kg–1, p.o.). (5) CCl4 plus AHE (400 mg kg–1, p.o). Rats received vehicle, CCl4, silymarin or AHE twice a week for 8 weeks. Serum AST (aspartate transaminase), LDH (lactate dehydrogenase), CK (creatine kinase), CK-MB (creatine kinase-MB isoenzyme) and cTnI (cardiac troponin) were measured to assess the heart damage markers. Serum levels of creatinine, urea, uric acid and BUN (blood urea nitrogen) were measured as markers of the renal function. Markers of oxidative stress in the cardiac and renal tissues were estimated by determining the levels of SOD (superoxide dismutase), GPx (glutathione peroxidase), CAT (catalase), GSH (reduced glutathione) and MDA (malondialdehyde). Heart and kidney tissues were investigated for histopathological changes. Results: Administration of CCl4 significantly increased the levels of cardiac and renal damage markers. Co-administration of CCl4 plus AHE significantly relieved the adverse effect of CCl4 in rat and reduced the increased serum levels of cardiac and renal damage markers. AHE compensated the deficits in the antioxidant defense mechanisms (SOD, GPx and CAT) and suppressed LPO (lipid peroxidation) in rat heart and kidney resulting from CCl4 administration. Moreover, histopathological changes induced with CCl4 in heart and kidney tissues of rat were also reduced with the co-administration of AHE. Conclusion: In this study, we have found that oral administration of AHE prevented CCl4-induced cardio- and nephrotoxicity by accelerating heart and kidney antioxidant defense mechanisms and down regulating the LPO near to the normal levels.