Objective: Alzheimer's disease (AD) is along with cognitive decline due to amyloid-β (Aβ) plaques, tau hyperphosphorylation, and neuron loss. Shenqi Xingnao Granules (SQXN), a traditional Chinese medicine, significantly ameliorated the cognitive function and daily living abilities of patients with AD. However, till date, no study has investigated the mechanism of action of SQXN on AD. The present study aimed to verify the effects of SQXN treatment on cognitive impairments and AD-like pathologies in APP/PS1 mice. Methods: Four-month-old APP/PS1 transgenic (Tg) mice were randomly divided into a model group and SQXN-treated (3.5, 7, 14 g/kg per day) groups. Learning-memory abilities were determined by Morris water maze and object recognition test. All mice were sacrificed and the brain samples were collected after 75 d. The soluble Aβ contents were detected by Elisa kit; The levels of expression of NeuN, APP, phosphorylated tau and related protein were measured by Western blotting; The inflammation factors were detected by the proinflammatory panel kit. Results: Four-month-old APP/PS1 mice were administered SQXN by oral gavage for 2.5 months. Using the Morris water maze tests and Novel object recognition, we found that SQXN restored behavioral deficits in the experimental group of Tg mice when compared with the controls. SQXN also inhibited neuronal loss (NeuN marker). SQXN treatment decreased soluble Aβ42 through inhibiting the expression of sAPPβ and BACE-1 without regulating full-length amyloid precursor protein (FL APP). Insulin degrading enzyme (IDE), the Aβ degrading enzyme, were increased by SQXN. In addition, SQXN reduced hyperphosphorylated tau protein levels and prevented excessive activation of p-GSK-3β in the brain of APP/PS1 mice. Compared with APP/PS1 transgenic negative mice, IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-12p70, KC/GRO and TNF-α were not obviously changed in the brain of 6.5-month-old APP/PS1 transgenic (Tg) mice. However, SQXN could inhibited the expression of IL-2. Conclusion: These results demonstrate that SQXN ameliorates the cognitive impairments in APP/PS1 mice. The possible mechanisms involve its inhibition of neuronal loss, soluble Aβ deposition, tau hyperphosphorylation and inflammation. © 2020 Tianjin Press of Chinese Herbal Medicines