Esophageal cancer (EC) involves many genomic, epigenetic and transcriptomic disorders, which play key roles in the heterogeneous progression of cancer. However, the study of EC with multi-omics has not been conducted. This study identified a high consistency between DNA copy number variations and abnormal methylations in EC by analyzing genomics, epigenetics and transcriptomics data and investigating mutual correlations of DNA copy number variation, methylation and gene expressions, and stratified copy number variation genes (CNV-Gs) and methylation genes (MET-Gs). The methylation, CNVs and expression profiles of CNV-Gs and MET-Gs were analyzed by consistent clustering using iCluster integration, here, we determined three subtypes (iC1, iC2, iC3) with different molecular traits, prognostic characteristics and tumor immune microenvironment features. We also identified 4 prognostic genes (CLDN3, FAM221A, GDF15 and YBX2) differentially expressed in the three subtypes, and could therefore be used as representative biomarkers for the three subtypes of EC. In conclusion, by performing comprehensive analysis on genomic, epigenetic and transcriptomic regulations, the current study provided new insights into the multilayer molecular and pathological traits of EC, and contributed to the precision medication for EC patients.