BACKGROUND: Given the lack of satisfactory clinical treatments for Alzheimer's disease (AD), a neurodegenerative condition detrimental to health, developing alternative therapies is critical. Tianqi Yizhi Granule (TQYZ) is a preparation used to treat AD based on traditional Chinese medicine theory, the latent mechanisms of which await elucidation. PURPOSE: This study sought to investigate the neuroprotective properties of TQYZ while exploring its potential therapeutic mechanisms using network pharmacology analyses and experimental validation. METHODS: Network pharmacology analyses were performed. Cognitive and neurodegenerative alterations were evaluated through behavioral tests and histological staining. For in vivo and in vitro experiments, short hairpin RNA sequences were transfected via adeno-associated virus vectors to verify the predicted mechanism. RESULTS: A total of 159 potential therapeutic targets of TQYZ overlapped with AD-related targets. In senescence-accelerated mouse prone 8 (SAMP8) mice, treatment with TQYZ significantly improved cognitive function, ameliorated neuronal damage and apoptosis, and upregulated the protein expression of PKC/ERK pathway members. TQYZ maintained the mitochondrial membrane potential, reduced the generation of reactive oxygen species, and inhibited neuronal apoptosis in Aβ CONCLUSIONS: TQYZ mitigates the pathological degeneration process and cognitive impairment in SAMP8 mice and suppresses mitochondrial dysfunction and apoptosis in HT22 cells treated with Aβ