Abstract: Objective Through the analysis of gene chip and bioinformatics, the differentially expressed genes (DEGs) and signal pathways related to the occurrence and development of malignant peripheral nerve sheath tumors (MPNSTs) were screened to provide new targets and directions for further research and treatment of MPNSTs. Methods The gene expression data set GSE66743 was downloaded from Gene Expression Omnibus (GEO) database, and the DEGs were obtained by analyzing the gene expression of benign neurofibroma and MPNSTs. Subsequently, the DAVID database was used for gene ontology (GO) function annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The STRING protein interaction database was used to construct the protein interaction network of DEGs and the Cytoscape software was used to identify the core genes from the protein interaction network. Finally, the core modules of the protein interaction network were screened by Cytoscape software and the KEGG enrichment analysis of the module design DEGs was carried out. Results A total of 493 up-regulated genes and 362 down-regulated genes were identified. GO analysis showed that DEGs was mainly involved in cell cycle, chromosome separation, mitotic cell cycle process, molecular function regulation and enzyme regulation activity. KEGG was mainly enriched in complement and coagulation cascade, proteoglycan, tyrosine metabolism, tumor necrosis factor (TNF) signaling pathway and chemokine signaling pathway, cell cycle, protein digestion and absorption, extracellular matrix (ECM)-receptor interaction and Fanconi anemia pathway. Ten core genes were screened by protein interaction network, and the enrichment analysis of the genes involved in the first three core modules showed that DEGs was mainly related to cell cycle, systemic lupus erythematosus, complement and coagulation cascade. Conclusions GO functional annotation and KEGG enrichment analysis reveal the potential pathogenesis of MPNSTs. The core genes and pathways provide potential diagnostic and therapeutic targets for MPNSTs.