Several studies have reported the role of CLCN4 in tumor progression. However, its mechanism remains to be thoroughly studied. The objective of this study was to explore the potential pathogenic role of CLCN4 in endometrial carcinoma (UCEC) with a better understanding of the pathological mechanisms involved. The potential roles of CLCN4 in different tumors were explored based on The Cancer Genome Atlas (TCGA), the expression difference, mutation, survival, pathological stage, Immunity subtypes, Immune infiltration, tumor microenvironment (TME), tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR) related to CLCN4 were analyzed. Then, the expression, prognosis, mutation, and functional enrichment of CLCN4 in UCEC were analyzed. Immunohistochemical experiment was used to verify the expression of CLCN4 in endometrial cancer tissues and normal tissues. In vitro, we knocked down of CLCN4 in HEC-1-A cells and performed CCK8, WB, RT-PCR, wound-healing, transwell assays to further validation of the molecular function. Results revealed that high expression of CLCN4 was observed in 20 cancer types of TCGA. CLCN4 expression correlates with poor survival in MESO, BLCA, THCA, especially UCEC tumors. CLCN4 expression was significantly associated with CD4+ T-cell infiltration, especially CD4+ Th1-cell. Immunohistochemical experiment reveals that CLCN4 is high expressed in endometrial tumors, in vitro experiment reveals that knockdown of CLCN4 inhibits the cells proliferation, migration and invasion. Our study is the first to offer a comprehensive understanding of the oncogenic roles of CLCN4 on different tumors. CLCN4 may become a potential biomarker in UCEC.