Tetrahydroxy stilbene glycoside (TSG), which is the primary active substance of Chinese herbal medicine called Polygonum multiflorum, has been acknowledged to alleviate Alzheimer's disease (AD)-induced learning disorder in the transgene mice. Because the microglia activation is really important during the AD progression, herein, we determined the effects of TSG on AD neuropathology, microglia polarization and its underlying mechanism. We used APP/PS1 mice along with immunohistochemistry and immunofluorescence techniques to evaluate the function of TSG as 60, 120 and 180 mg/kg on Aβ deposition, neuronal loss and microglia polarization induced by AD. Additionally, we assessed the effects of TSG on TREM2 signalling using both molecular docking and Western blot analysis. TSG was found to promote neuronal survival and decrease Aβ deposition in APP/PS1 mice. Moreover, TSG reduced microglia M1 polarization and modulated the TREM2/PI3K/AKT signalling pathways. TSG could reduce neuronal impairment by mediating the microglia polarization by TREM2/PI3K/AKT signalling pathway in APP/PS1 mice and is a latent pharmacological research direction for the therapy in the patients with AD.