Glioblastoma (GBM) is the most aggressive and common primary brain tumor in adults, yet effective therapeutic strategies remain limited. In this study, we integrated transcriptomic and clinical data from the Chinese Glioma Genome Atlas (CGGA) and found that high UBE3A expression is significantly associated with poor prognosis in GBM. As an E3 ubiquitin ligase within the ubiquitin-proteasome system (UPS), UBE3A plays a crucial role in maintaining protein homeostasis and cellular processes. Functional assays in GBM cell lines demonstrated that UBE3A knockdown markedly reduced cell proliferation, colony formation, migration, and invasion. Mechanistically, UBE3A physically interacted with SV2A and promoted its ubiquitination, indicating that SV2A is one of its potential substrates. Either UBE3A depletion or SV2A overexpression reduced ERK and p38 phosphorylation, indicating suppression of MAPK signaling, and was accompanied by increased apoptotic signaling (enhanced PARP cleavage and caspase-3 activation). These findings indicate that UBE3A and SV2A drive GBM progression mainly via MAPK pathway regulation. Although additional studies of the UBE3A-SV2A axis and downstream MAPK signaling are needed, this axis may represent a promising therapeutic target in glioblastoma.