To explore the effectiveness and mechanism of modified Erxian Decoction(MED) in the treatment of spinal cord injury(SCI) based on network pharmacology and other methods.Methods:The effectiveness of the prescription was verified via animal experiments.The component and target prediction and network analysis were carried out with the methods of network pharmacology.The chemical components and targets of the prescription were searched against the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and UniProt,and the therapeutic targets of SCI were collected from GeneCards and Drugbank.The protein-protein interaction was analyzed in String and then Cytoscape_v3.7.1 was used to build a network.Metascape was used for gene ontology(GO) annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment.Results:The animal experiments showed that MED significantly alleviated SCI and increased the behavioral score of hindlimb in rats.A total of 5 353 genes were identified to be associated with the 18 Chinese herbal medicines in MED.After re-screening,319 genes were obtained.A total of 3 237 genes were screened out for SCI,among which 2 638 remained after re-screening.MED and SCI shared 216 common genes.Chuanxiong Rhizoma,Angelicae Sinensis Radix,Salviae Miltiorrhizae Radix et Rhizoma,Cyperi Rhizoma,Corydalis Rhizoma,Epimedii Folium,and Curcumae Radix in the prescription may mediate the cyclic adenosine monophosphate(cAMP),phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt),mitogen-activated protein kinase(MAPK),and tumor necrosis factor(TNF) signaling pathways through AKT serine/threonine kinase 1(AKT1),MAPK3,nuclear factor-kappa-B-inhibitor alpha(NFKBIA),Fos proto-oncogene,AP-1 transcription factor subunit(FOS),phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma(PIK3CG) and other key genes to treat SCI.Conclusion:MED has significant effect on the treatment of SCI.The network pharmacology-based study indicates that the multi-target and multi-component MED may treat SCI through cAMP and PI3K/Akt signaling pathways.