SUMOylation, a post-translational protein modification, plays a crucial role in regulating various biological processes. Dysregulation of SUMOylation has been linked to glioblastoma progression, impacting key signaling pathways. This review summarizes the current knowledge on SUMOylation's role in glioma malignancy, highlighting its influence on cell cycle regulation, PKB/AKT signaling pathway, and microRNA expression. Our work identifies Ubc9 as a promising therapeutic target due to its role in enhancing SUMOylation, promoting glioblastoma aggressiveness, and facilitating tumor proliferation. Additionally, SAE1 correlates with glioblastoma grade and affects cell cycle regulators, while SUMOylation stabilizes CDK6, driving the G1/S transition. Targeting these pathways with inhibitors, such as topotecan and chlorogenic acid, may provide novel treatment strategies. Furthermore, SUMOylation-driven alterations in transcription factors and DNA repair mechanisms contribute to therapy resistance. Understanding these mechanisms could pave the way for innovative interventions in glioblastoma management.