Yizhijiannao granules have been shown to improve cognitive function in Alzheimer’s disease patients. The present study sought to explore the mechanisms involved in the cognitive enhanc-ing effects ofYizhijiannao granule. Senescence-accelerated mouse prone 8 mice with learning and memory disorders were intragastrically treated withYizhijiannao granule for 8 weeks. Mice intragastrically treated with double distilled water for 8 weeks were considered as the control group. 2D gel electrophoresis was used to isolate total protein from the temporal lobe of senes-cence-accelerated mouse prone 8 mice, and differential protein spots were obtained by mass spectrometry. Thirty-seven differential protein spots were found in the temporal lobe area of both groups. Ten protein spots were identiifed: high mobility group box 1, dimethylarginine dimethylaminohydrolase-1, neuroglobin, hemoglobin beta adult major chain, peroxiredoxin-6, coiflin-1, lfotillin 1, peptidylprolyl isomerase A, voltage-dependent anion channel-2 and chap-eronin containing TCP1, and subunit 2. Among other functions, these proteins are separately involved in the regulation of amyloid beta production, oxidative stress, neuroinflammation, regulation of tau phosphorylation, and regulation of neuronal apoptosis. Our results revealed thatYizhijiannao granule can regulate the expression of various proteins in the temporal lobe of senescence-accelerated mouse prone 8 mice, and may be therapeutically beneifcial for the treat-ment of Alzheimer’s disease.