Sichuan pepper, a well-known traditional Chinese spice, is popularly used in Chinese cuisine. In this study, the antioxidant activities of Sichuan pepper water extract (SP) were evaluated both chemically [in 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl (DPPH) assay] and biologically [in 2,2-azobis-(2-amidinopropane) (AAPH)-induced haemolysis assay]. The protective effect of SP against H2O2-induced cytotoxicity in primary Sprague Dawley rat hepatocytes was investigated by using cell viability assay, nuclear staining, intracellular reactive oxygen species (ROS) measurement and flow cytometry. It was found to possess high total phenolic content as assessed by the Folin-Ciocalteu method. The antiapoptotic effect of SP may be mediated, in part, by significantly inhibiting intracellular ROS generation and depletion of the mitochondrial membrane potential. SP was also found to enhance the cellular antioxidant defense system through up-regulating heme oxygenase-1 expression. SP is an effective antioxidant that can be consumed regularly as a functional food for the prevention of oxidative stress-related liver diseases.