The hepatoprotective activity of the aqueous extract of the roots of Decalepis hamiltonii was investigated against ethanol-induced oxidative stress and liver damage. Pretreatment of rats with aqueous extract of the roots of D. hamiltonii, single (50, 100 and 200mg/kg b.w.) and multiple doses (50 and 100mg/kg b.w. for 7 days) significantly prevented the ethanol (5g/kg b.w.) induced increases in the activities of the serum enzymes, aspartate and alanine transaminases, alkaline phosphatase and lactate dehydrogenase in a dose dependent manner. Parallel to these changes, the root extract inhibited the ethanol-induced oxidative stress in the liver by suppressing lipid peroxidation and protein carbonylation and maintaining the levels of antioxidant enzymes and glutathione. The biochemical changes were consistent with histopathological observations suggesting marked hepatoprotective effect of the root extract. The protective effect of the root extract against hepatotoxicity of alcohol was more pronounced by the multiple dose pretreatment. Hepatoprotective activity of the aqueous extract of the roots of D. hamiltonii could be attributed to the antioxidant effect of the constituents and enhanced antioxidant defenses.