Ethnopharmacological relevance: The whole plant of Fagonia schweinfurthii (Hadidi) Hadidi (Family: Zygophyllaceae) is used in variety of diseases including hepatic ailments in deserts and dry areas of India. Aim of the study: To evaluate antioxidant and hepatoprotective activity of ethanolic extract from Fagonia schweinfurthii (Hadidi) Hadidi (FSEE) in carbon tetrachloride (CCl 4 ) induced hepatotoxicity in HepG2 cell line and rats. Materials and methods: In vitro antioxidant activity was determined by DPPH, ABTS radicals and hydrogen peroxide methods. In vitro cytotoxicity and hepatoprotective potential of FSEE were evaluated using HepG2 cells. Based on the cytotoxicity assay, FSEE (50, 100, 200 g/ml) was assessed for hepatoprotective potential against CCl 4 induced toxicity in HepG2 cell line by monitoring cell viability, aspartate aminotransferase (AST), alanine aminotransaminase (ALT), lactate dehydrogenase (LDH) leakage, lipid peroxidation (LPO) and glutathione level (GSH). Further, in vivo hepatoprotective activity of FSEE was evaluated against CCl 4 induced hepatotoxicity in male Wistar albino rats. Rats were pre-treated with FSEE (200mg, 400mgkg - 1 day - 1 p.o.) for 7 days followed by a single dose of CCl 4 (1.0ml/kg, i.p.) on 8th day. Silymarin was used as positive control. After 24h of CCl 4 administration, various biochemical parameters like aspartate aminotransferase (AST), alanine aminotransaminase (ALT), alkaline phosphatase (ALP), total bilirubin (TB) and total protein (TP) levels were estimated in serum. The antioxidant parameters like superoxide dismutase (SOD) activity, catalase (CAT) activity, glutathione (GSH) content and malondialdehyde (MDA) level in the liver homogenate were determined. Histopathological changes in the liver of different groups were also studied. Results: The FSEE possessed strong antioxidant activity in vitro. The results indicated that CCl 4 treatment caused a significant decrease in cell viability. The CCl 4 -induced changes in the HepG2 cells were significantly ameliorated by treatment of the FSEE. FSEE significantly prevented CCl 4 induced elevation of AST, ALT, ALP, TB, and CCl 4 induced decrease in total protein in rats. FSEE treated rat liver anti-oxidant parameters (SOD, CAT, MDA and GSH,) were significantly antagonized for the pro-oxidant effect of CCl 4 . Histopathological studies also supported the protective effect of FSEE. Conclusion: The results of this study revealed that FSEE has significant hepatoprotective activity. This effect may be due to the ability of the extract to inhibit lipid peroxidation and increase in the anti-oxidant enzymatic activity.