We demonstrated that both TMEFF2 and SMOC-2 were highly expressed in EC and were associated with a shortened survival rate, dismal outcome, and poor prognosis in EC patients. While SOX17 expression was related to a favorable outcome and its downregulation was associated with dismal EC patient's survival. Moreover, we concluded that TMEFF2, SMOC-2, and SOX17 could affect malignant behaviors such as proliferation, invasion, and migration by controlling the EMT process and CSCs criteria in EC cells making them novel beneficial biomarkers and targeted therapies for EC patients. Our findings might be of great significance for explaining the pathogenesis and prognosis of EC, which might help in the identification of therapeutic targets for EC