This study was designed to evaluate the protective role of exogenous CoQ10 and DHEA and their combination on CCl4 induced hepatotoxicity in adult male rats. Thirty adult male rats 225-250 grams, 12-14 weeks old were used in this study and randomly divided into five equal groups, 6 animals each as in the following: Control group (G1): 6 male rats received orally DMSO 0.5ml/animal/day, First treated group (T1): 6 male rats received daily CCl4 1ml/kg (1:1 olive oil, IP), Second treated group (T2): 6 male rats received CCl4 1ml/kg and after 1hour injected daily with CoQ10 200 mg/kg IP, Third treated group (T3): 6 male rats received CCl4 1ml/kg and after 1hour injected daily with DHEA  25 mg/kg IP, Fourth treated group (T4): 6 male rats received CCl4 1ml/kg and after 1hour injected daily with a combination of CoQ10 200 mg/kg + DHEA 25 mg/kg IP. The experiment lasted for 28 successive days. The obtained results illustrated that male rats received CCl4 (1ml/kg) caused a significant increase in hepatic function enzymes AST, ALT, and ALP, as well as MDA levels, and caused a significant decrease in antioxidant enzyme activity GPx, SOD, and CAT levels. Also, CCl4 caused various degrees of liver damage such as dilation and congestion of the central vein with hemorrhage, clear fatty degeneration, and infiltration of inflammatory cells compared to the control group. Whereas, the group that treated with CoQ10 200 mg/kg and DHEA 25 mg/kg showed a significant decrease (P< 0.05) in serum AST, ALT, and ALP as well as MDA value, and a significant increased in GPx, SOD with declined in CAT levels compared to the group treated with CCl4 intoxication. It is also observed from the results that the combination of CoQ10 and DHEA caused a highly significant (P < 0.05) declined in AST, ALT, and ALP as well as MDA levels, and significant elevated in GPx, SOD, and declined in CAT, and almost return to normal level compared to control. As well, the histopathological examination on the liver revealed that rats treated with CoQ10 and DHEA and their combination had normal central vein and hepatocytes compared to groups treated with CCl4 due to anti-oxidant, anti-inflammatory, and anti-apoptotic properties. It has been concluded that CoQ10 and DHEA have an evident protective effect against liver damage induced by CCl4 through improving antioxidant enzyme activity in CCl4 treated group leading to a declined MDA level and reduced lipid peroxidation.