High-grade gliomas (HGGs) are brain and spinal cord tumours. Most adults diagnosed with an aggressive HGG called glioblastoma (GBM) die within two years, and diffuse intrinsic midline glioma (DIPG), a rare form of paediatric HGG, is 100% lethal, demonstrating an urgent need to understand better HGG pathophysiology to develop effective therapies. Ion channels, protein pores within membranes that conduct metal ions, are crucial to HGG pathophysiology and are targets of several clinically approved drugs that pass the blood-brain barrier. Specifically, the activity of one family of ion channels, voltage-gated sodium channels (VGSCs), has been implicated in aiding cancer progression, metastasis, and invasion in non-nervous system cancers, but their contribution to HGG progression is unknown. Here, using a combination of analyses, including single-cell and spatial transcriptomics, proteomics, and immunohistochemistry, we profiled the expression landscape of the VGSC family in GBM and DIPG patient tumours. We found that VGSCs typically expressed in the central nervous system are upregulated by invasive glioma cells at the tumour periphery and form excitatory glutamatergic connections with neighbouring neurons, whose activity is known to drive tumour growth. RNA, protein, and electrophysiological analysis of patient-derived cell lines demonstrate differences in VGSC pore-forming α subunit expression between GBM and DIPG cells, indicating potential opportunities for targeted drug interventions. Further, in vitro invasion assays showed that VGSC blockers that specifically target sodium currents that remain activated at positive membrane potentials effectively block the intrinsic invasiveness of DIPG but not GBM cell lines. Taken together, our findings indicate that VGSC blockers may be an adjunct therapeutic option for addressing HGG, disrupting the pathological interactions between neurons and glioma cells, while specifically slowing DIPG cell invasiveness.