Alzheimer's disease (AD) is the most common type of dementia with an insidious onset and slow progression. Kai-Xin-San (KXS) has been reported to be effective in improving cognitive impairment in AD. However, the mechanism is still confused. In this study, we employed APP/PS1 mice to explore the neuroprotective mechanism of KXS. Forty-eight male APP/PS1 mice were randomly divided into model group, Kai-Xin-San groups (0.7, 1.4 and 2.8 g/kg/d, p.o.) and the wild-type mice were assigned to the normal control group (n=12 in each group). Y-maze and novel object recognition (NOR) tests were carried out after continuous intragastric administration for 2 months. The abilities of learning, memory and new object recognition in the APP/PS1 mice were enhanced significantly after KXS treatment. KXS can reduced the deposition of Aβ40 and Aβ42 in APP/PS1 mice brain. KXS decreased the levels of serum inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). KXS increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) significantly, while inhibited the contents of reactive oxygen species (ROS) and malondialdehyde (MDA) significantly. In addition, we also detected Wnt/β-catenin signaling related proteins, such as Wnt7a, β-catenin, low-density lipoprotein receptor-related protein 6 (LRP6), glycogen synthase kinase-3β (GSK-3β), nuclear factor kappa-B (NF-κB), postsynaptic density 95 (PSD95), microtubule associated protein-2 (MAP-2) and ER stress (IRE1 pathway) related proteins, such as inositol-requiring enzyme 1 (IRE1), phosphorylated IRE1(p-IRE1), spliced X-box-binding protein 1 (XBP1s), immunoglobulin binding protein (BIP), protein disulfide isomerase (PDI) in hippocampus. Results showed that KXS decreased the expressions of GSK-3β, NF-kB, p-IRE1/IRE1 ratio, XBP1s and BIP, increased the expressions of Wnt7a, β-catenin, LRP6, PSD95, MAP2 and PDI. In conclusion, KXS improved cognitive impairment by activating Wnt/β-catenin signaling, inhibiting IRE1/XBP1s pathway in APP/PS1 mice.