Objective To comprehensively analyze the extracellular proteomic information during the 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 through proteomics technology. Methods A rat model of Agkistrodon halys bite was established by injecting Agkistrodon halys venom solution into gastrocnemius muscle. Animals were divided into control, model, positive control group treated with anti-venom serum, and 717 Jiedu Decoction (low, medium, and high doses) groups. First, extracellular matrix (ECM) was prepared by chemical detergent-mediated decellularization, followed by proteomic detection and bioinformatics analysis., then the expression of target proteins was verified by Western Blot (WB). Results A total of 6523 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 traditional Chinese medicine group, including 25 up-regulated and 11 down-regulated proteins. 7 proteins showed common differential expression in the two comparison groups. Gene Ontology (GO) enrichment analysis revealed that DEPs were significantly enriched in response to stress, defense response, proteolysis, biological interactions and fibrinolysis, peptidase regulator activity, protease binding. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis found that the DEPs were mainly enriched in the signal pathways of ECM-receptor interaction, regulation of actin cytoskeleton, neutrophil extracellular trap formation, complement and coagulation cascades, fluid shear stress and atherosclerosis, metabolic pathways, etc. Protein functional interaction network analysis revealed that proteins such as Vitronectin, Fibrinogen alpha chain, Kininogen 1, Plasminogen, Prothrombin, Integrin α2b are located at key nodes in the network. (2) WB 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 positive control group treated with anti-venom serum and 717 Jiedu Decoction groups (low, medium, and high doses) downregulated the expression of Kininogen 1 and Fetuin-B (P < 0.01), while upregulated the expression of Vitronectin and and Integrin α2 (P < 0.01), with dose-dependent effects observed among all dose of 717 Jiedu Decoction groups. Conclusions The regulation of local ECM remodeling in rats after Agkistrodon halys bite by 717 Jiedu Decoction may be related to signaling pathways such as ECM-receptor interaction, regulation of actin cytoskeleton, and neutrophil extracellular trap formation. DEPs such as Vitronectin, Integrin α2, Kininogen 1, and Fetuin-B may be key targets.