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Objective: To explore the mechanism of Xi Shao Formula (XSF) in treating neuropathic pain (NP) through metabolomics and network pharmacology. Methods: A chronic compression injury (CCI) of the sciatic nerve model was established to simulate NP; following CCI induction, animals were gavaged with normal saline, XSF, or the positive control drug pregabalin for 21 days. Serum metabolomics methods and enrichment analysis were employed to identify significant serum metabolites and metabolic pathways influenced by XSF. Through network pharmacology and liquid chromatograph with mass spectrometer analyses, the active compounds and targets of XSF for treating NP were analyzed. Additionally, the serum metabolomics and network pharmacology analysis results were integrated, drawing network diagrams illustrating the relationships between “target, metabolic pathway, and metabolite” using Cytoscape 3.9.1. The findings were further validated through molecular docking. Results: Based on metabolomics, 11 differential endogenous metabolites were identified as potential biomarkers related to XSF for treating NP; functional enrichment analysis revealed eight metabolic pathways in XSF for treating NP. Based on integrated metabolomics and network pharmacology, the “monoamine oxidase A (MAOA)/MAOB/tyrosinase (TYR)–tyrosine metabolism pathway–gentisic acid” emerged as a significant network pathway in XSF for treating NP. The molecular docking results revealed high affinity and stable interaction between the active components of XSF and their respective target, namely MAOA, MAOB, and TYR (binding energy