Background: Malignant peripheral nerve sheath tumors (MPNSTs) are an aggressive form of sarcomas with a poor prognosis and limited treatment options. Therefore, new therapeutic targets are urgently needed to identify novel drugs. Methods: Based on the Gene Expression Omnibus database, an integrated analysis was performed to identify differentially expressed genes (DEGs) in MPNSTs compared to neurofibromas (NFs). Then functional enrichment analyses, protein-protein interaction (PPI) network construction, and hub gene selection were conducted. We explored DEG-guided repurposable drugs to treat MPNST based on the Library of Integrated Network-Based Cellular Signatures (LINCS) database. Furthermore, the binding affinity between predicted drug candidates and the MPNST-associated hub gene was calculated using molecular docking. Results: We identified 89 DEGs in common with all three MPNSTs datasets. In the PPI networks, twist family bHLH transcription factor 1 (Twist1) with higher node degrees was further evaluated as a therapeutic target. Cytochalasin-d, cabozantinib, everolimus, refametinib, and BGT-226 were extracted from the LINCS database, which showed lower normalized connectivity scores (–1.88, –1.81, –1.78, –1.76, and –1.72, respectively) and was considered as drug candidates. In addition, the results of molecular docking between the five drugs and Twist1 showed a binding affinity of –6.61, –7.03, –7.73, –3.94, and –7.07 kcal/mol, respectively. Conclusions: Overall, our results describe the importance of Twist1 in MPNST pathogenesis. Everolimus was also found to be a potential therapeutic drug for MPNSTs.