Endometrial cancer (EC) patients with Diabetes Mellitus (DM) always have a poor prognosis. Estrogen-related receptor α (ERRα) is known as the metabolic-related prognostic factor for EC. However, the mechanism linking glycolipid metabolism dysfunction mediated by ERRα to poor prognosis of EC with DM is still unclear. In vitro, high-glucose (HG) levels showed enhancement of ERRα expression, cell proliferation, and inhibition of the autophagic lysosomes and apoptosis by flow cytometry analysis, transmission electron microscopy, and CCK-8 assays. Mechanistically, lose-and-gain function assay, DNA sequencing, and CO-IP revealed HG increased ERRα expression to promote the transcription of HK2 and HMGCS1, which were the key rate-limiting enzyme of glycolysis-cholesterol synthesis and their metabolites suppressed the autophagy-lysosomal pathway in an ERRα-dependent manner. Furthermore, CO-IP and molecular dynamics simulation uncovered the protein residues (ARG 769(HK2) vs. ARG 313(HMGCS1)) of HK2 and HMGCS1 could bind to p62 to form stable protein complexes involved in the autophagy-lysosomal pathway. In EC tissue from patients with comorbid DM, ERRα was significantly higher expressed compared to EC tissue from patients without evidence for DM (p < 0.05). The 3D EC organoid model with HG stimulation showed that the cell viability of XCT790 + carboplatin treatment was similar to that of metformin+carboplatin treatment, while the obviously bigger volume of organoids was more visible in the metformin+carboplatin group, indicating the therapy of XCT790 + carboplatin had the better inhibition of EC organoids with the same carboplatin dose. Besides insights into the interaction of HG and the autophagy-lysosomal pathway via ERRα, our present study points out the potential benefit of targeting ERRα in patients with EC with dysregulation of glucose and cholesterol metabolism.