This dataset contains the raw proteomics data (LC-MS/MS) generated from mouse brain tissue to investigate the neuroprotective mechanisms of Yixin Yangshen Granules (YXYS) in Alzheimer’s disease (AD). The samples were analyzed using an Orbitrap Fusion Lumos Tribrid mass spectrometer. Abstract: Alzheimer's disease (AD) involves amyloid and tau pathology with neuroimmune dysregulation. This study aimed to elucidate the multi-target mechanisms of YXYS in AD using integrated transcriptomic and proteomic profiling. Results highlighted that YXYS ameliorates AD via multi-target modulation of HIF-1 and AGE-RAGE pathways, restoring neuro-immune homeostasis and reducing oxidative stress, neuroinflammation, and hypoxia.