Long-term effects of Ganoderma lucidum (GL) on memory and oxidative stress of senescence-accelerated mice (SAM) were investigated. Senescence-resistant (R1) and prone (P8) strains of SAM were fed GL diets, premixed with low (20 mg/kg/day, T1) or high (200 mg/kg/day, T2) levels of GL powder for 9 months starting from young (3 months of age) or for 5 months starting from old (7 months of age). After the final feeding at 12 months of age, all animals were subjected to passive avoidance test for the evaluation of memory function. In addition, the changes in hepatic thiobarbituric acid-reactive substance (TBARS) and glutathione were analyzed. SAMP8 fed GL diets from old age (7 months) exhibited the improvement of memory, although GL rather inhibited the memory function of both SAMR1 and SAMP8 mice fed diets from young (3 months of age). Hepatic TBARS contents were decreased in SAMP8 fed high GL diet for 9 months and in SAMR1 fed low GL diet for 5 months. Hepatic glutathione content was also remarkably increased in SAMR1 following both feeding periods, and less extent in SAMP8 fed diet for 5 months of age. Taken together, it is proposed that GL extracts may play an anti-aging role through antioxidant action, and thereby may improve the senescence-related memory dysfunction.