Objective To comprehensively analyze extracellular proteomic information during toxicity induced by Agkistrodon halys venom and the detoxification process of 717 Jiedu Decoction, aiming to explore new target molecules involved in local tissue damage and repair. Methods A rat model of Agkistrodon halys(A. halys) bite was established by injecting A. halys venom into the gastrocnemius muscle of SD rats. Animals were divided into control, model, anti-venom ( positive drug), and low, medium, and high dose 717 Jiedu Decoction (717-L, -M,-H) groups. Extracellular matrix (ECM) was prepared by chemical detergent-mediated decellularization, followed by proteomic detection and bioinformatics analysis. The expression of target proteins was verified by Western blot. Results A total of 6 523 proteins were identified through proteomic analysis, with 606 extracellular proteins screened. (1) Compared with the model group, there were 36 expressed proteins (DEPs) in the high dose of 717 Jiedu Decoction group, including 25 up-regulated and 11 down-regulated proteins. Seven proteins showed common differential expression between the control group and the model group, as well as between the model group and the 717-H group. Gene Ontology enrichment analysis revealed that DEPs involved in responses to stress, defense response, proteolysis, biological interactions, fibrinolysis, peptidase regulator activity, and protease binding were significantly enriched. Kyoto Encyclopedia of Genes and Genomes pathway analysis found that the DEPs were mainly enriched in the signal pathways of ECM-receptor interaction, regulation of the actin cytoskeleton, neutrophil extracellular trap formation, complement and coagulation cascades, fluid shear stress and atherosclerosis, and metabolic pathways. Functional interaction network analysis revealed that proteins such as Vitronectin, Fibrinogen alpha chain, Kininogen 1, Plasminogen, Prothrombin, and Integrin α2b were located at key nodes in the network.(2) Western blot validation was performed on the common DEPs (Kininogen 1 and Fetuin-B) and the central node proteins in the protein functional interaction network (Vitronectin and Integrin α2). Compared with the model group,the anti-venom and 717 Jiedu Decoction groups ( low, medium, and high doses) downregulated Kininogen 1 and fetuin-B expression (P<0. 01), while upregulating the Vitronectin and integrin α2 expression (P<0. 01), with dosedependent effects observed among all doses of 717 Jiedu Decoction groups. Conclusions The regulation of local ECM remodeling in rats after A. halys bite by 717 Jiedu Decoction may be related to signaling pathways such as ECMreceptor interaction, regulation of the actin cytoskeleton, and neutrophil extracellular trap formation. DEPs such as Vitronectin, Integrin α2, Kininogen 1, and Fetuin-B may be key targets.