Objective To study the effect of hesperetin early prevention on learning and memory ability and its mechanism related to TLR2 、NF-κB in Alzheimer's disease (AD) model mice. Methods Twelve 3-month-old C57/B6 mice were used as blank control group. 48 APP/PS1 double transgenic mice were randomly divided into four groups: model group, low dose group, middle dose group, high dose group (n=12 in each group). The low, middle and high dose groups were given hesperidin 20mg/kg, 40mg/kg and 80mg/kg respectively. The blank control group and the model group were given the same amount of carboxymethylcellulose sodium (each day for 6 months). The learning and memory ability was measured with Morris water maze. HE staining was used to observe the neuronal damage in CA1 region of hippocampus. Western blot was used to detect the contents of TLR2 and NF-κB protein in brain tissue of mice. Results Compared with the blank control group, the escaping latency of the model group was significantly prolonged, the times crossing the hidden platform was significantly decreased (P<0.05), and the neuronal damage in the hippocampal CA1 region was obviously increased. The contents of TLR2 and NF-κB protein were significantly increased (P<0.05). Compared with the model group, the escaping latency of mice in the low, middle and high dose groups was significantly shortened, the times crossing the hidden platform was significantly increased (P<0.05), and the neuronal damage in the hippocampal CA1 region was mild. The content of TLR2 and NF-κB protein decreased significantly (P<0.05). Conclusion Hesperetin early prevention can significantly improve the learning and memory ability and the injury of hippocampal neurons in APP/PS1dE9 mice, and its mechanism might be related to the down-regulation of TLR2 and NF-κB protein expression.