Differentially methylated genes (DMGs) play a crucial role in the etiology and pathogenesis of esophageal squamous cell carcinoma (ESCC). This study aimed to ascertain aberrant DMGs and pathways by comprehensive bioinformatics analysis. We downloaded the gene expression microarray of GSE51287 from the Gene Expression Omnibus (GEO). Aberrant DMGs were obtained using the GEO2R tool. Gene ontology (GO) analysis and Kyoto Encyclopedia of Gene and Genome pathway enrichment analyses were performed on selected genes by using the Database for Annotation Visualization and Integrated Discovery. A protein–protein interaction (PPI) network was constructed with the Retrieval of Interacting Genes (STRING) and visualized in Cytoscape. Then, the modules in the PPI networks were analyzed with Molecular Complex Detection, and the hub genes derived from the PPI networks were verified by using the Cancer Genome Atlas. A total of 271 DMGs, including 173 hypermethylated genes, were enriched in the biological processes of peptidyl-tyrosine phosphorylation, positive regulation of transcription from RNA polymerase II promoters, and autophosphorylation. Pathway analysis enrichment revealed cancer, PI3K-Akt, and Ras signaling pathways, and 98 hypomethylated genes were enriched in the biological processes of the immune response, extracellular matrix disassembly, and macrophage differentiation. Pathway enrichment showed rheumatoid arthritis, cytokine–cytokine receptor interaction, and toxoplasmosis. Furthermore, bioinformatics analysis indicated feasible aberrant DMGs and pathways in ESCC. The results provided valuable information on the pathogenesis of ESCC. The significant DMGs may provide novel insights into their potential predictive and prognostic value as methylation-based biomarkers for the precise diagnosis and treatment of ESCC.