Glioblastoma (GB) and brain metastases (BM) are the most common brain tumors in adults and are invariably associated with a dismal outcome. These highly malignant tumors share common features including increased invasion and migration of the primary or metastatic brain cancer cells, whose triggering mechanisms are largely unknown. Emerging evidence has suggested that the ubiquitin-conjugating enzyme E2C (UBE2C), essential for controlling cell cycle progression, is overexpressed in diverse malignancies, including brain cancer. This review highlights the crucial role of UBE2C in brain tumorigenesis and its association with higher proliferative phenotype and histopathological grade, with autophagy and apoptosis suppression, epithelial-to-mesenchymal transition (EMT), invasion, migration, and dissemination. High expression of UBE2C has been associated with patients’ poor prognosis and drug resistance. UBE2C has also been proven as a promising therapeutic target, despite the lack of specific inhibitors. Thus, there is a need to further explore the role of UBE2C in malignant brain cancer and to develop effective targeted therapies for patients with this deadly disease.