This study presents an epigenetically defined neural signature in high-grade gliomas that independently predicts patient survival. The signature, derived from reference signatures of neural cells, classifies glioblastoma samples into low- and high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals a high abundance of malignant stem cell-like cells, primarily of the neural lineage, in these tumors. These cells are classified as neural-progenitor-cell-like, astrocyte-like, and oligodendrocyte-progenitor-like. High-neural glioblastoma cells form neuron-to-glioma synapses in vitro and in vivo, and show an unfavorable survival after xenografting. In patients, a high-neural signature is associated with decreased overall and progression-free survival. High-neural tumors also exhibit increased functional connectivity in magnetoencephalography and resting-state functional MRI and can be detected via DNA analytes and brain-derived neurotrophic factor in plasma. The prognostic importance of the neural signature is validated in diffuse midline gliomas. The study highlights the significance of the nervous system in brain tumor progression and suggests that high-neural gliomas may require maximized surgical resection for improved outcomes.This study presents an epigenetically defined neural signature in high-grade gliomas that independently predicts patient survival. The signature, derived from reference signatures of neural cells, classifies glioblastoma samples into low- and high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals a high abundance of malignant stem cell-like cells, primarily of the neural lineage, in these tumors. These cells are classified as neural-progenitor-cell-like, astrocyte-like, and oligodendrocyte-progenitor-like. High-neural glioblastoma cells form neuron-to-glioma synapses in vitro and in vivo, and show an unfavorable survival after xenografting. In patients, a high-neural signature is associated with decreased overall and progression-free survival. High-neural tumors also exhibit increased functional connectivity in magnetoencephalography and resting-state functional MRI and can be detected via DNA analytes and brain-derived neurotrophic factor in plasma. The prognostic importance of the neural signature is validated in diffuse midline gliomas. The study highlights the significance of the nervous system in brain tumor progression and suggests that high-neural gliomas may require maximized surgical resection for improved outcomes.