This study investigated the effect of isoflavone aglycone (IA) on the learning and memory performance of senescence-accelerated mice, and explored its neural protective mechanism. Results showed that SAM-P/8 senescence-accelerated mice treated with IA performed significantly better in the Y-maze cognitive test than the no treatment control (P less than 0.05). The cortex AchE activity, serum SOD and GSH-Px activities were notably higher (P less than 0.05). MDA concentration and the [beta]-secretase activity in the hippocampal tissue were both lower (P less than 0.05). Additionally, the number of hippocampal neurons was increased and cell morphology was significantly improved. Data suggested that IA could indirectly increase concentration of the cholinergic neural transmitter Ach through regulation of AchE, therefore improving the central cholinergic function and enhancing the learning and memory ability. By reducing the [beta]-secretase activity, IA could decrease the formation and deposition of insoluble Adebris, relieve the resulted toxicity and damage to neurons, and thereby effectively protect the nervous system.