The Rumex Aquaticus Herba extract containing quercetin-3-β-D-glucuronopyranoside (ECQ) has been reported to exhibit various pharmacological activities, including anti-inflammatory and anti-oxidative effects. This plant has been traditionally used for the treatment of diarrhea, disinfestation, edema and jaundice, and as an antipyretic drug. The aim of the present study was to investigate the ability of ECQ to protect against oxidative damage and to determine its signaling mechanism in AGS cells. The protein expressions of heme oxygenase-1 (HO-1) and nuclear factor-erythroid 2 related factor 2 (Nrf2) were measured by Western blots. Cell viability was measured by MTT assay. Intracellular reactive oxygen species (ROS) levels were measured using 2',7'-dichlorofluorescein diacetate. Glutathione peroxidase levels were measured using kits. The protein expressions of HO-1 and its upstream mediator, Nrf2, increased after ECQ treatment. The HO-1 inhibitor, ZnPP, repressed the protective effect of ECQ on H2O2-induced cell damage. We found that LY294002, a specific PI3 K/Akt inhibitor, suppressed ECQ-induced HO-1 expression. ECQ significantly attenuated H2O2-induced cytotoxicity and ROS generation. Also, ECQ enhanced the antioxidant enzyme activities of glutathione peroxidase. These results suggest that ECQ exerts a cytoprotective effect against H2O2-induced oxidative stress by upregulation of Nrf2/HO-1 via the PI3 K/Akt pathway.