Gliomas represent some of the most aggressive and therapeutically challenging brain tumors, characterized by their high invasiveness and resistance to conventional chemotherapeutic regimens. Current treatments often fail to simultaneously impede proliferative signaling pathways and preserve the integrity of the cellular membrane, both critical factors in glioma progression and tumor resilience. This study evaluates the neuroprotective and adjuvant therapeutic potential of nuciferous compounds derived from Juglans regia, notably enriched in polyunsaturated fatty acids (PUFAs) and phenolic derivatives, known for their bioactivity and antioxidative properties.In vitro assays on established glioma cell lines revealed that bioactive fractions of Juglans regia extracts significantly inhibited cellular proliferation by 47% after 48 hours of treatment (p < 0.001), highlighting their potent anti-proliferative effect. Concurrently, biochemical assessments demonstrated a marked attenuation of oxidative damage to the cellular membrane, evidenced by a 61% reduction in thiobarbituric acid reactive substances (TBARS), underscoring membrane lipid peroxidation mitigation. Comprehensive chemical profiling via gas chromatography–mass spectrometry (GC–MS) identified docosapentaenoic acid (DPA) as a predominant PUFA within the active fractions. Subsequent molecular docking studies revealed favorable binding affinities of DPA towards key glioma-associated protein targets, including the mutant epidermal growth factor receptor variant III (EGFRvIII) and protein kinase C alpha (PKCα). These interactions suggest a plausible mechanism wherein DPA modulates oncogenic proliferative signaling axes and promotes lipid bilayer stabilization, potentially enhancing membrane resilience against oxidative insult. Collectively, this multidisciplinary investigation elucidates the therapeutic relevance of Juglans regia-derived polyunsaturated compounds as neuroprotective agents with the capacity to complement existing glioma therapies. Our findings advocate for further in vivo validation and pharmacological characterization, aiming to harness these natural bioactives for integrated glioma management strategies focused on both tumor suppression and membrane stabilization. Keywords: Juglans regia, glioma, polyunsaturated fatty acids, neuroprotection, membrane lipid peroxidation, EGFRvIII, PKCα, anti-proliferative mechanisms, oxidative stress mitigation