Abstract: Objective To explore the effect of quercetin on the cognitive function in the hippocampus of amyloid precursor protein/presenilin 1 (APP/PS1) mice, and to find new methods and targets for the treatment of Alzheimer's disease (AD). Methods Male APP/PS1 transgenic mice (n=16) were randomly divided into a model group (AD group, n=8) and a quercetin intervention group (QUE group, n=8); the littermate wild-type male mice were used as control (Control group, n=8). The 3-month-old mice in QUE group were fed with quercetin diet (2.5 mg/g), the Control group and AD group were fed with normal diet. Morris water maze test was carried out at the age of 9 months to detect the spatial learning ability of mice in each group. The protein expression of toll like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) p65 in the hippocampus was determined by immunofluorescence and Western blot respectively. The mRNA expression of tumor necrosis factor-α (TNF-α), IL-1β, IL-6, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in the hippocampus were detected by quantitative real-time reverse transcription PCR (qRT-PCR). Results Compared with the Control group, the time and distance in the target quadrant in the AD group was significantly reduced (P<0.05), the escape latency was prolonged (P<0.05) in Morris water maze test, the protein expression of TLR4 and NF-κB p65 in the hippocampus was increased (P<0.05), and the mRNA expression of TNF-α, IL-1β, IL-6, COX-2 and iNOS in the hippocampus was also significantly increased (P<0.05). Compared with the AD group, the time and distance in the target quadrant in the QUE group were significantly increased (P<0.05) , while the escape latency was shortened in Morris water maze test (P<0.05); the protein expression of TLR4, NF-κB p65 and the expression of TNF-α, IL-1β, IL-6, COX-2, iNOS in the hippocampus were all decreased (P<0.05). Conclusions Quercetin can significantly improve the learning and memory ability and inflammatory response of APP/PS1 mice, and its mechanism may be related to the inhibition of TLR4/NF-κB signaling pathway in hippocampus.