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Background/Objectives: Glioblastoma remains the most aggressive and lethal form of brain cancer, with no effective cure to date. The molecular mechanisms sustaining its development and relentless proliferation are still not fully understood. SETMAR, a protein lysine methyltransferase involved in various DNA repair and chromatin processes, has been reported as dysregulated in several cancers, including glioblastoma. Interestingly, S-SETMAR, a shorter isoform of SETMAR, has been suggested to antagonize the oncogenic properties of the full-length protein. Here, we explored the cellular and molecular consequences of S SETMAR overexpression in glioblastoma cells. Methods: We compared native glioblastoma cells (8MGBA) with a recombinant 8MGBA line stably overexpressing αS SETMAR, a stable form of S-SETMAR, using complementary cellular and molecular approaches. Results: Overexpression of αS-SETMAR markedly prolonged the cell cycle duration (from 27 to 37 hours), leading to a significant decrease in cell proliferation. Unexpectedly, αS-SETMAR triggered genomic alterations characterized by an increased DNA content and extensive chromosomal instability, including aneuploidy, chromoanasynthesis-like rearrangements, and tripolar mitoses. Moreover, αS-SETMAR-expressing cells displayed heightened sensitivity to stress conditions mimicking chemotherapy and radiotherapy, resulting in increased apoptosis. Conclusions: Our findings identify αS-SETMAR as a dual modulator of glioblastoma cell fate - simultaneously slowing proliferation and promoting chromosomal instability while enhancing vulnerability to genotoxic stress. These results suggest that αS SETMAR could serve as both a prognostic marker and a potential therapeutic tool in glioblastoma management.