Preclinical Research Nine known phenolic compounds were isolated from an aqueous methanolic extract of Acrocarpus fraxinifolius Weight and Arn leaves (AFL) family Fabaceae. This extract of AFL contained approximately 169 mg gallic acid/g as assessed by HPLC. The AFL extract had marginal antitumor activity (IC50 > 200 µL/mL) but showed a concentration-dependent hepatoprotective effect against CCl4 -induced hepatotoxicity in vitro. Cell viability was increased, ALT and AST activity declined and reduced GSH concentration and SOD activity were restored as compared with silymarin. In vivo concurrent administration of AFL extract (500 mg/kg po) showed a hepatoprotective effect against gamma irradiation and CCl4 as evidenced by reduction of TNF-α, interleukin-6, malondialdehyde, nitric oxide, DNA fragmentation, caspase-3 activity, and downregulation of its m-RNA level and decreased proapoptotic protein Bax expression. AFL extract enhanced glutathione peroxidase, superoxide dismutase, and catalase activities, reduced glutathione concentrations and upregulated the expression of antiapoptotic Bcl-2. The extract could ameliorate hepatic injuries induced by gamma irradiation and CCl4 in rats suggesting potent hepatoprotective activity. Drug Dev Res 78 : 210-226, 2017. © 2017 Wiley Periodicals, Inc.