Alzheimer’s disease (AD) is a neurodegenerative disorder for which no effective treatments are currently available. PANoptosis is a coordinated cell death pathway involving pyroptosis, apoptosis, and necroptosis. Astragaloside IV (AS-IV) is a bioactive saponin derived from Astragalus membranaceus. Behavioral performance was evaluated using the Morris water maze and open field tests, while neuronal damage was assessed by Nissl staining. The expression levels of Aβ, IL-18, and PANoptosis-related proteins were analyzed by Western blot. Immunofluorescence was performed to assess the co-localization of PANoptosis-associated proteins with neurons in the hippocampal region. In addition, the effects of AS-IV on the expression of PANoptosis-related proteins were examined in Aβ-induced HT22 cells. AS-IV improved spatial memory performance and alleviated anxiety-like behaviors in AD mice. Furthermore, AS-IV treatment significantly reduced Aβ protein levels and attenuated neuronal loss in the hippocampus. Key markers of PANoptosis were downregulated following AS-IV treatment. Immunofluorescence revealed strong co-localization between PANoptosis-associated proteins and neurons. In vitro, AS-IV also inhibited the Aβ-induced upregulation of PANoptosis-related proteins in HT22 cells. Collectively, these results indicate that AS-IV exerts neuroprotective effects in AD models, which may be associated with reduced Aβ protein deposition, attenuated neuronal loss, and the regulation of PANoptosis-related proteins in the hippocampus.