Background: One defining feature of various aggressive cancers, including glioblastoma multiforme (GBM), is glycolysis upregulation, making its inhibition a promising therapeutic approach. One promising compound is 2-deoxy-d-glucose (2-DG), a d-glucose analog with high clinical potential due to its ability to inhibit glycolysis. Upon uptake, 2-DG is phosphorylated by hexokinase to 2-DG-6-phosphate, which inhibits hexokinase and downstream glycolytic enzymes. Unfortunately, therapeutic use of 2-DG is limited by poor pharmacokinetics, suppressing its efficacy. Methods: To address these issues, we synthesized novel halogenated 2-DG analogs (2-FG, 2,2-diFG, 2-CG, and 2-BG) and evaluated their glycolytic inhibition in GBM cells. Our in vitro and computational studies suggest that these derivatives modulate hexokinase activity differently. Results: Fluorinated compounds show the most potent cytotoxic effects, indicated by the lowest IC₅₀ values. These effects were more pronounced in hypoxic conditions. ¹⁹F NMR experiments and molecular docking confirmed that fluorinated derivatives bind hexokinase comparably to glucose. Enzymatic assays demonstrated that all halogenated derivatives are more effective HKII inhibitors than 2-DG, particularly through their 6-phosphates. By modifying the C-2 position with halogens, these compounds may overcome the poor pharmacokinetics of 2-DG. The modifications seem to enhance the stability and uptake of the compounds, making them effective at lower doses and over prolonged periods. Conclusions: This research has the potential to reshape the treatment landscape for GBM and possibly other cancers by offering a more targeted, effective, and metabolically focused therapeutic approach. The application of halogenated 2-DG analogs represents a promising advancement in cancer metabolism-targeted therapies, with the potential to overcome current treatment limitations.