The role of Epiplakin1 (EPPK1) in colon adenocarcinoma (COAD) was analyzed through a comprehensive evaluation of its expression, methylation, genetic mutations, and prognostic implications. A significant up-regulation of EPPK1 expression in COAD malignant cells compared to normal control samples was observed using data from the UALCAN database. EPPK1 expression was found to be elevated across different cancer development stages, racial groups, genders, and age groups, emphasizing its crucial role in cancer proliferation. Validation of EPPK1 expression through the GEPIA2.0 dataset further confirmed its overexpression in COAD when compared to normal samples. The analysis revealed dysregulation across all four stages of cancer development, with the highest expression in stage IV and the lowest in stage II. Additionally, promoter methylation analysis demonstrated a fundamental relationship between COAD samples and normal controls, revealing significant methylation patterns across different clinical parameters, including cancer stages, race, gender, and age. Overall survival (OS) and disease-free survival (DFS) analysis using the KM plotter showed a strong association between high EPPK1 expression and worse survival outcomes in COAD patients. Conversely, low EPPK1 expression was linked to better OS and DFS. Genetic mutation analysis using cBioPortal identified minimal EPPK1 mutations in COAD, predominantly truncating and missense mutations, highlighting their relevance to EPPK1 dysregulation in COAD. These findings underscore the important role of EPPK1 in COAD development and proliferation, suggesting its potential as a therapeutic target and prognostic marker. Further exploration of EPPK1’s molecular mechanisms and its involvement in the COAD microenvironment may reveal new pathways for targeted treatments and precision medicine strategies against this challenging disease.