Commelina diffusa is a plant rich in antioxidant compounds, used in traditional medicine to treat many diseases. This study aimed to evaluate the hepatoprotective and antioxidant activities of aqueous and methanolic extracts of Commelina diffusa. Total phenolic and flavonoids content of extracts were determined. Hepatotoxicity was induced in rats by administration of gentamicin (80 mg/kg, i.p.) once daily for 10 days. Simultaneously, extracts were given at doses of 100 and 200 mg/kg, p.o. At the end of treatment, body weight of rats was measured; blood and liver tissues were collected for biochemical and histopathological analysis. The results showed that aqueous and methanolic extracts of C. diffusa contain significant amounts of total phenols and flavonoids. These extracts significantly decreased (p<0.05 to p<0.001) liver weight, activity of transaminases and alkaline phosphatase and the levels of malondialdehyde, bilirubin, LDL cholesterol, triglycerides and total cholesterol. In contrast they significantly increased (p<0.05 to p< 0.01) the body weight of rats, the levels of HDL cholesterol, total protein, glutathione and the activity of catalase and superoxide dismutase. Histopathological examination revealed that extracts protected liver tissues against cell infiltration and centrolobular necrosis induced by gentamicin. These results suggest that Commelina diffusa could protect against hepatotoxic effects of gentamicin.