Esophageal squamous cell carcinoma (ESCC) is considered as the dominant type of malignancy in both Western and Asian countries. The increase in trends of smoking and drug addiction is proportional to cases of ESCC and this has to be addressed. The delay in the detection of ESCC can be countered by using the proteogenomics approach that helps in identifying novel genes and tracking them back to the genome. In this top-down proteomic approach, we propose a customized protein sequence database generated using genomics information of ESCC mapped to mass spectrometry-based proteomics data to derive peptides and protein-coding genes that are missing from the current annotations for esophageal cancer. We carried out global genomics and proteomics analysis using proteogenomics approach and identified unpredicted peptides and their biological functions. A customized database containing six-frame-translated whole-genome sequence data of esophageal cancer was produced to map with mass spectrometry-derived proteomic data. On mapping, we obtained a list of sixteen unique peptides and their respective genes involved in ESCC. On further investigation, the functional site prediction suggests detailed evidence of phosphorylation playing a major role in the modification of the identified peptides. Overall, our study suggested that further analysis of post-translational modifications (PTM) and single nucleotide polymorphism would give more comprehensive information that aids in understanding the disease mechanism and cancer prognosis. Hence the impacts of delay in the detection of esophageal cancer can be countered using proteogenomic approach.