BACKGROUND : Cucumis ficifolius A. Rich is a perennial prostrate herb that stems up to 1 m long. Its root is widely used in traditional medicine to treat various diseases including liver diseases. Yet, scientific evidence is lacking to verify its ethno medicinal claims. OBJECTIVE : The present study was conducted to assess the hepatoprotective and radical scavenging activity of 80% methanol crude extract and different fractions of Cucumis ficifolius root. METHODS : Radical scavenging activity was done applying the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay while hepatoprotective activity was assessed using pre- and post-treatment models of carbon tetrachloride (CCl4)-induced liver injury in Swiss albino mice of either sex weighing 25-30 g. A single oral dose of 2000 mg/kg was used for acute toxicity study, doses of 125, 250, and 500 mg/kg were used in the pre-treatment model, and 500 mg/kg of extract and chloroform fraction were used in the post-treatment model. Biochemical markers and histopathological parameters were used to measure hepatoprotective activities. RESULTS : C. ficifolius crude extract and its solvent fractions showed strong radical scavenging activity and the chloroform fraction had the highest activity. No sign of toxicity was shown in an acute toxicity test of the extract. Hepatoprotective activity evaluation on the crude extract by a pre-treatment model with 125, 250, and 500 mg/kg doses revealed a significant (p < 0.05) reduction of the serum level of CCl4-induced liver enzyme markers at the highest tested dose (500 mg/kg). The chloroform fraction that had highest radical scavenging activity and the crude extract, both at 500 mg/kg, were again evaluated in a post-treatment model and the results revealed that both the extract and the chloroform fraction demonstrated significant (p < 0.05) hepatoprotective activities which support the results of the pre-treatment model. CONCLUSIONS : The present study verified the hepatoprotective potentials of C. ficifolius extract and its chloroform fraction which might be, at least in part, through radical scavenging action.