Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with no effective treatment currently available. The Methods: In this study, senescence-accelerated mouse prone 8 (SAMP8) mice, an AD model, were treated with GSPM (low: 117 mg/kg, high: 234 mg/kg) or donepezil (1.3 mg/kg) via gavage for 2 months. Cognitive function was assessed using the Morris water maze. Hippocampal morphology was evaluated by H&E staining, and neuronal apoptosis was detected by TUNEL assay. Microgliosis and astrogliosis were analyzed by Iba1 and GFAP immunohistochemistry. Levels of phosphorylated Tau, Aβ1-42, Aβ1-40, inflammatory cytokines, oxidative stress markers, and senescence markers were measured. Gut microbiota composition was analyzed by 16S rRNA sequencing. Results: GSPM treatment improved cognitive function, reduced hippocampal tissue damage, and decreased neuronal apoptosis in AD mice. It alleviated neuroinflammation by reducing microgliosis and astrogliosis and lowered the levels of p-Tau protein and Aβ accumulation in both the hippocampus and cerebrospinal fluid. Additionally, GSPM reversed the enhanced inflammation, oxidative stress, and neuronal senescence observed in AD mice. Furthermore, GSPM modulated gut microbiota composition by reducing microbial diversity and restoring the Conclusion: Our data demonstrated that GSPM exhibits protective effects on AD via suppressing the inflammation, oxidation, and senescence, possibly through regulating the Sirt1 signaling. These findings provided a novel therapeutic approach for AD.