Abstract：Objective：To observe the effect of icariin on toll-like receptor 4(TLR4)/myeloid differentiation factor 88(MyD88) /nuclear factor kappa-light-chain-enhancer of activated B(NF-κB p65) signaling pathway in hippocampus in rat models of Alzheimers disease(AD). Methods： A total of 60 SD rats were randomly divided into the sham operation group，the model group，the positive control group(0.25 mg/kg Donepezil Hydrochloride)，and the icariin groups of low dosage，medium dosage and high dosage(30.00，60.00 and 120.00 mg/kg respectively). Except the rats in the sham operation group，all rats were injected with Aβ25- 35 to establish AD models. After four- week treatment， Morris water maze was used to test the spatial learning ability； the activities of superoxide dismutase(SOD) and catalase(CAT)， and malondialdehyde (MDA) in hippocampus were detected with the kit； enzyme- linked immunosorbent assay was used to measure the levels of inflammatory factors [tumor necrosis factor(TNF- α)， interleukin- 1β(IL- 1β)， interleukin- 6(IL- 6)] and neurotransmitters [acetylcholinesterase(AchE)， acetylcholine(Ach)， choline acetyltransferase(ChAT)] in hippocampus； Hematoxylin and Eosin(HE) staining was used to observe the pathological changes of hippocampal neurons in rats； Western blot was used to detect the protein expressions of TLR4， MyD88， NF- κB p65， cleaved cysteinyl aspartate specific proteinase- 3(CCaspase3)， and B- cell lymphoma- 2[Bcl- 2，Bcl- 2- associated X protein(Bax)] in hippocampus. Results： The escape latency in Morris water maze of rats in the model group was prolonged when compared with that in the sham operation group(P＜0.05)，and the number of platform crossings and the time spent in the original platform quadrant in the model group were decreased(P＜0.05). The levels of Ach，ChAT，SOD and CAT in hippocampus and the protein expression of Bcl- 2 in rats in the model group were significantly decreased when compared with those in the sham operation group，and the levels of AchE，MDA，TNF- α，IL-β and IL-6，and the protein expressions of Bax，C- Caspase-3，TLR4，MyD88 and NF-κB p65 were significantly increased(P＜0.05). In the CA1 region of the hippocampus in rat models， there were disordered arrangement of neurons， loose neuronal cell structure， karyopyknosis of neurons， and the formation of vesicles. The escape latency in Morris water maze of rats in the positive control group，and the icariin groups of medium dosage and high dosage was shortened when compared with that in the model group(P＜0.05)，and the number of platform crossings and the time spent in the original platform quadrant in the model group were increased(P＜0.05). The levels of Ach，ChAT，SOD and CAT in hippocampus and the protein expression of Bcl- 2 in rats in the positive control group， and the icariin groups of medium dosage and high dosage were significantly increased when compared with those in the model group，and the levels of AchE，MDA，TNF-α，IL-β and IL-6，and the protein expressions of Bax，C- Caspase-3， TLR4， MyD88 and NF- κB p65 were significantly decreased(P＜0.05). After administration， neuronal damage in the CA1 region of the hippocampus was improved to various degrees in rats of each administration group. Conclusion：Icariin can regulate TLR4/MyD88/NF-κB p65 signaling pathway to relieve oxidative stress and inflammatory responses in hippocampus of rats and inhibit neuronal apoptosis， thus alleviates AD.