Background: Momordica charantia is used in China for its jianghuo (heat-clearing and detoxifying) effects. The concept of shanghuo (the antonym of jianghuo, excessive internal heat) in traditional Chinese medicine is considered a type of stress response of the body. The stress process involves internal organs, especially the liver. Objective: We hypothesized that Momordica charantia water extract (MWE) has a hepatoprotective effect and can protect the body from stress. The aim of this study was to investigate the possible effects of MWE against liver injury in restraint-stressed mice. Design: The mice were intragastrically administered with MWE (250, 500 and 750?mg/kg bw) daily for 7?days. The Normal Control (NC) and Model groups were administered distilled water. A positive control group was intragastrically administered vitamin C 250?mg/kg bw. After the last administration, mice were restrained for 20?h. Results: MWE reduced the serum AST and ALT, reduced the NO content and the protein expression level of iNOSin the liver; significantly reduced the mitochondrial ROS content, increased the mitochondrial membrane potential and the activities of mitochondrial respiratory chain complexes I and II in restraint-stressed mice. Conclusions: The results indicate that MWE has a protective effect against liver injury in restraint-stressed mice. Abbreviations: MWE: Momordica charantia water extract; M. charantia: Momordica charantia L.; ROS: reactive oxygen species; NO: nitric oxide; iNOS: inducible nitric oxide synthase; IL-1β: interleukin-1 beta; TNF-α: tumor necrosis factor alpha; IL-6: interleukin 6; IFN-γ: interferon gamma; VC: vitamin C; ALT: alanine transaminase; AST: aspartate aminotransferase; GSH: glutathione; GSH-PX: glutathione peroxidase; MDA: malondialdehyde; BCA: bicinchoninic acid; TBARS: thiobarbituric acid reactive substances; Trolox: 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; JC-B: Janus Green B; DW: dry weight; FC: Folin-Ciocalteu; GAE: gallic acid equivalents; bw: body weight; NC: normal control group; Model: restraint stress model group; VC: positive control vitamin C group, 250 mg/kg bw; MWEL: Momordica charantia water extract low-dose group, 250 mg/kg bw; MWEM: Momordica charantia water extract middle-dose group, 500 mg/kg bw; MWEH: Momordica charantia water extract high-dose group, 750 mg/kg bw; HE: hematoxylin and eosin; ORAC: total oxygen radical absorbance capacity; ABAP: dihydrochloride; ATP: adenosine triphosphate.