Abstract: Background and Objective: Hepatotoxicity caused by hepatoxins is very perilous state of affairs for metabolism of liver. The present study was aimed to investigate hepatoprotective activity on flavonoids rich extracts of (Cucumis dipsaceus Ehrenb.) fruits. Methodology: In vitro hepatoprotective was activity performed on HepG2 cell line by MTT assays for methanolic and water extract to verify cytotoxicity. Acute oral toxicity was plaid on both extracts to know about minimum and maximum dosing by using either sex Wistar albino rats. In vivo hepatoprotective activity of both extract was evaluated against CCl4 induced hepatic damage in liver of Wistar albino rats. Biochemical parameters were studied on blood serum obtained after collecting and clotting of blood form the retro-orbital sinus plexus under mild ether anesthesia and then centrifuged at 3500 rpm for 15 min. In vivo antioxidant enzymes activity was evaluated on superoxide dismutase, glutathione, catalase and 2-thiobarbituric acid reactive substances/malondialdehyde (TBARS/MDA) on liver homogenate of rats. Values obtained from every investigation were statistically analyzed by one way ANOVA followed by Tukey’s multiple comparison tests using Graph Pad Instat software package. The difference was considered significant if p<0.05. Results: The results on HepG2 cell line by MTT assays of both extracts were significantly dose dependent. The results of biochemical parameters were found to be significantly normalized from reduced release of these SGOT, SGPT, SALP, billirubin, total protein of CCl4 treated rats. The results obtained from in vivo antioxidant enzymes assays for SOD, CAT, GSH and TBARS/MDA were performed on homogenized part of rat liver after complete dosing were significant than CCl4 treated group. Histopathological studies were performed on sliced of isolated rat liver after dosing for 7 days. Conclusion: The results found from in vivo antioxidant activity and hepatoprotective activity showed that both extracts were hepatoprotective and same was supported by histopathological studies on liver of pretreated rat and CCl4 rats.