Abstract: Objective To investigate the potential molecular mechanisms underlying the decline in cognitive function induced by remimazolam in aged rats, based on proteomic analysis. Methods An aging rat model was established by subcutaneous injection of D-galactose. The modeled rats were randomly divided into two groups: a remimazolam group and a model group. Cognitive function was evaluated using the Morris water maze test. Hippocampal tissues were collected for proteomic analysis. Results Compared with the model group, the remimazolam group exhibited significantly prolonged escape latency (P<0.05). Proteomic analysis identified 20 differentially expressed proteins in the hippocampus of the remimazolam group, including 8 upregulated and 12 downregulated proteins. Gene Ontology (GO) enrichment analysis revealed that these proteins were mainly involved in biological processes, molecular functions, and cellular components. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that remimazolam primarily affected signaling pathways related to lipoic acid metabolism, extracellular matrix-receptor interactions, vitamin digestion and absorption, and chemical carcinogenesis-DNA adduct formation. Conclusions Remimazolam may modulate the expression of hippocampal proteins such as Ptpn1, Snap25, and Snrpf, and influence lipoic acid metabolism and related signaling pathways, thereby leading to cognitive decline in aged rats.