Objective To explore the key genes in the occurrence and development of tuberculous ulcer(TU)through bioinformatics, and provide new ideas for the study of TU. Methods Datasets of previous acquired gene sequencing and GSE83456 downloaded from gene expression omnibus (GEO) were selected. Common differentially expressed genes were screened by R software and performed enrichment analysis via gene ontology (GO) as well as Kyoto encyclopedia of genes and genomes (KEGG). Protein-protein interaction (PPI) network was constructed and visualized by STRING and Cytoscape software. Key genes were screened out by cytoHubba plug-in, then verified by gene set enrichment analysis (GSEA). 60 patients with TU in a hospital from July 2021 to March 2022 and 60 healthy physical examination persons during the same period were selected. Key genes in serum were verified by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Results 19 common differentially expressed genes were screened out, mainly enriched in antiviral immune response, monocyte chemotaxis regulation, interferon-β function, NOD-like receptor signaling pathway, and infectious diseases, etc. GBP1 was screened out as a key gene after PPI analysis, and verified to be highly correlated with TU by GSEA. qRT-PCR confirmed that GBP1 expression was high in the serum of TU patients, and decreased significantly after 2 weeks treatment (both P < 0.001). Conclusion GBP1 may be a biomarker for TU diagnosis and potential target for treatment.