Endometrial carcinoma (EC) is one of the most common gynecological cancers with a poor prognosis. Therefore, clarifying the details of the molecular mechanisms is of great importance for EC diagnosis and clinical management. Interferon-stimulated gene 15 (ISG15) plays an important role in the development of various cancers. However, its role in EC remains unclear. High ISG15 expression was observed in EC, which was associated with poor clinical outcomes and pathological stage of patients with EC, thus representing a promising marker for EC progression. Further exploratory analysis revealed that the elevated ISG15 levels in EC were driven by aberrant DNA methylation, independent of copy number variation and specific transcription factor aberrations. Accordingly, knockdown of ISG15 by small interfering RNA attenuated the malignant cellular phenotype of EC cell lines, including proliferation and colony formation in vitro. Finally, investigation of the molecular mechanisms indicated that ISG15 promoted the cell cycle G1/S transition in EC. Furthermore, ISG15 promoted EC progression by activating the MYC proto-oncogene protein signaling pathway. Moreover, ECs with high levels of ISG15 harbored a more vital immune escape ability, evidenced not only by significantly less invasive CD8(+) T cells, but also higher expression of T cell inhibitory factors, such as programmed death-ligand 1. These results suggest a tumor-promoting role of ISG15 in EC, which may be a promising marker for diagnosis, prognosis and therapeutic immunity.