Objective： Sesamin is a lignan food functional component from sesame seed and possess multiple bioactives， including antioxidant， anti-inflammatory and anti-depression. Here， we investigated the neuroprotective effects sesamin on preventing cognitive deficits in Alzheimer’s disease（AD） mouse model. Methods： The 6-month old female APP/PS1 transgenic mice were dietary supplemented with sesamin（0.05%， weight/weight） for 3 months. Results： It has been found that dietary supplementation of sesamin alleviated the cognitive impairment. Sesamin reduced Aβ accumulation and the expression of PSD-95 in mice brain. In addition， sesamin suppressed the microglial activation by inhibiting IBA-1 expression in hippocampus. Moreover， sesamin treatment significantly downregulated APP expression and activated the AKT/IDE signaling in the cortex. Conclusion： The results indicated that sesamin could alleviated the cognitive disorders in APP/PS1 mice. This study provides a clue for the potential beneficial neuroprotective effects for sesamin supplementation.