Several vegetables have been shown to possess cytoprotective and antioxidant effects with various mechanisms of action. The aim of this study was to determine the antioxidant effects and mechanism underlying of Syzygium gratum, a dietary and herbal plant commonly found in the Southeast Asia. Additionally, its effects on the induction of endogenous antioxidant defensive system were also investigated. Results showed that the leaf extract possessed an exceptionally strong antioxidant and intracellular oxygen radical scavenging activity in both aqueous and ethanolic extracts. The plant aqueous extract was further studied in C57BL/6J mice to evaluate its effects in vivo. The extract was well tolerated by the animals throughout the 30 days of study. The cytoprotective enzyme, heme oxygenase (HO-1) activity was significantly increased in the high dose-treated animals (1 g/kg/day). Consistent with the enzymatic activity, the expression of HO-1 mRNA tended to increase in those mice. There was no significant increase in hepatic γ-glutamylcysteine ligase (γ-GCL) activity, glutathione levels and GCL mRNA expression. Taken together, this study provides evidence that S. gratum exhibits potent direct antioxidant properties and can induce cytoprotective enzyme in vivo. Consumption of S. gratum may provide a health benefit against oxidative stress and other related disorders.