Objective Excessive aluminum (Al) exposure impairs neurocognitive function in humans and animals. Epidemiologic studies have shown a potential linkage between chronic Al exposure and Alzheimer’s disease. The present study aims to evaluate the effects of tetrahydroxy stilbene glucoside (TSG), the extract from herbal medicine Polygoni Multiflori, on cognitive impairment and the over-expression of hippocampal amyloid precursor protein (APP) induced by chronic exposure to Al in rats. Methods Rats were treated with 0.3% aluminum chloride (AlCl3) prepared in the drinking water for 90 d. AlCl3-treated animals were then randomly assigned to receive vehicle, TSG (4 g/kg), or Vitamin E (VE; 40 mg/kg) treatment for 5 months. VE served as a positive control. The effect of TSG was evaluated by passive avoidance task, and APP expression was evaluated by Western blotting. Results Following exposure to AlCl3 for 90 d, animals displayed a striking decrease (〉80%) in step-through latency in the passive avoidance task and a significant increase in the expression of APP in the hippocampus. Both TSG and VE significantly ameliorated the performance impairment in the passive avoidance task, and suppressed the over-expression of APP. Moreover, the effects of TSG, but not of VE, were in a time-dependent manner. Conclusion TSG may possess therapeutic effects against Alzheimer’s disease.