Background: Esophageal squamous cell carcinoma (ESCC) does not have distinct and highly sensitive biomarkers, making its diagnosis difficult. Consequently, identifying dependable biomarkers is critical, as these indicators can facilitate accurate ESCC diagnosis and enable effective prognostic evaluation. Methods: ESCC datasets (GSE29001, GSE20347, GSE45670, and GSE161533) were sourced from the GEO, and the Limma package identified differentially expressed genes (DEGs). To characterize co-expression network, weighted gene co-expression network analysis (WGCNA) was performed, allowing for the identification of relevant co-expression modules. To assess the biological pathways of intersecting genes, we performed pathway enrichment analysis using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). The Support Vector Machine Recursive Feature Elimination (SVM), along with Least Absolute Shrinkage and Selection Operator (LASSO) regression, was applied to identify clinical biomarkers. Finally, the differences of immune cell infiltration were also detected. Results: 1,019 genes were derived by integrating DEGs with co-expressed module genes. KEGG and GO revealed a strong association between these genes and processes such as chemotaxis and IL-17 signaling pathways. Two hub genes ( Conclusion: Collectively,