Endometrial cancer is a common gynecologic cancer, which is relevant to many differentially expressed genes. Centrosomal protein 55 (CEP55) was proved to be aberrantly expressed in several cancers. However, the function of CEP55 in endometrial cancer remains largely uncertain. The differentially expressed genes in endometrial cancer were analyzed by GEO datasets. CEP55 expression and its correlation to aggressive behaviors and diagnosis were analyzed by TCGA and the Human Protein Atlas databases. The association between CEP55 expression and 5-year overall survival in endometrial cancer was predicted using Kaplan-Meier Plotter database. Cell proliferation and apoptosis were determined by western blotting, EdU staining, TUNEL staining, and LDH release. CEP55-related targets were predicted by LinkedOmics and analyzed by KEGG pathway analysis using KOBAS. Foxo1 level was detected by western blotting. CEP55 expression was increased in endometrial cancer. The upregulated CEP55 was associated with tumor invasion, histologic grade, histological type and poor prognosis in endometrial cancer. CEP55 knockdown decreased PCNA and CDK2 levels and inhibited cell proliferation. Moreover, CEP55 downregulation promoted cell apoptosis, LDH release and increased cl-caspase-3/caspase-3 level. CEP55-related targets were enriched in Foxo1 signaling. CEP55 silencing increased the transcription activity of Foxo1. Inhibition of Foxo1 activity reversed the effect of CEP55 knockdown on cell proliferation and apoptosis. In conclusion, CEP55 knockdown repressed cell proliferation and facilitated apoptosis by regulating the Foxo1 signaling in endometrial cancer.