Four groups of 1-mo-old male senescence-accelerated mice (SAMP8) were fed Polygonum multiflorum Thunb. (PM) extract for 18 wk to determine the effect of PM on memory ability and histopathological changes in mice. The baseline diet consisted of a casein diet group, and the three test diets were supplemented with 50% ethanol, 95% ethanol, or water extracts of PM. It was found that the mice fed with PM extracts had better active shuttle avoidance response, fewer vacuole numbers, less lipofuscin in the hippocampus, and lower MDA concentrations in the brain. Our data showed that the ethanol PM extract groups (both 50% and 95% groups) had lower lipofuscin percentages and MDA concentrations, and higher total thiol concentrations than the water PM extract group. The 50% ethanol PM extract group showed significantly lower total cholesterol and triglyceride values than the other groups, but the HDL cholesterol level was the same. These results suggest that dietary supplementation with either ethanol or water extracts can reduce brain pathological changes and promote learning and memory ability. The performance of PM extracts depended on the extraction method, with ethanol extraction tending to obtain better results.