Scutellariae radix (SR) is an herbal medicine used for the treatment of inflammatory diseases. To investigate whether the SR water extract has a hepatoprotective effect in mice fed a high fat diet with chronic alcohol consumption, ICR mice were fed one of the following diets: a control diet (CD, 16% fat), a high fat diet (HFD, 40% fat), a high fat diet with either ethanol (HFDE, 25% v/v, ad libitum) alone or ethanol with SR extract (HFDESR, 100 mg/kg, p.o.) for 28 days, respectively. The combination of high fat diet with ethanol exposure induced hepatic damage that was manifested by a significant increase in the activities of functional enzymes, alanine transaminase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH) in serum. Also, the liver and visceral fat weights were increased and the lipid profiles in serum and liver homogenate including triglyceride, total cholesterol, LDL-cholesterol were significantly deteriorated. The SR supplements significantly reversed these altered parameters to near the values of the CD mice. Specifically, the expression of 3-hydroxy-3-methylglutaryl-coenzymeA (HMG-CoA) reductase in liver homogenate was significantly lowered in the HFDESR group compared with that of either the HFD or HFDE groups, which revealed that the SR extract could afford protection in the alleviation of high fat and alcoholic liver damage.