Polyhydroxy stilbenes have been reported to possess various biological activities and have potential for treatment of Alzheimer's disease. Tetrahydroxystilbene glucoside is one of the major polyhydroxy stilbenes, which provides the underlying therapeutic activities for neuroprotective actions in various experimental conditions. This study investigates the impact of a tetrahydroxystilbene glucoside remedy for cognitive disorder and oxidative stress in Aβ_1-42-induced Alzheimer's disease mice and clarifies the mechanisms of action through the Kelch-like erythroid cell-derived protein with conserved non-coding homology-associated protein 1/nuclear factor erythroid 2-related factor pathway. It was found that the swimming time of Aβ_1-42-induced mice treated with tetrahydroxystilbene glucoside (30, 60, and 120 mg/kg) was significantly increased in the target quadrant of a Morris water maze experiment and the number of avoidances was increased during a passive avoidance experiment, Moreover, tetrahydroxystilbene glucoside attenuated Aβ_1-42-induced memory impairment. However, the locomotor and exploratory activity of mice were not affected. Tetrahydroxystilbene glucoside clearly decreased the levels of malondialdehyde and oxidized glutathione in both hippocampus and cortex compared with the Aβ_1-42-treated group, and also clearly increased the level of glutathione and activities of catalase and superoxide dismutase in those tissues. The results of this study demonstrated that tetrahydroxystilbene glucoside increased nuclear factor erythroid 2-related factor and heme oxygenase-1 protein expression and decreased Kelch-like erythroid cell-derived protein with conserved non-coding homology-associated protein 1 protein expression in a concentration-dependent manner in Aβ_1-42-treated mice, which involved the Kelch-like erythroid cell-derived protein with conserved non-coding homology-associated protein 1/nuclear factor erythroid 2-related factor antioxidant pathway in hippocampus and cerebral cortex tissue. These results demonstrate that tetrahydroxystilbene glucoside as a natural drug that may provide a potential treatment for Alzheimer's disease.