Selenium nanoparticles (SeNPs) show promise in protecting the brain from stroke by targeting signaling and metabolic pathways. Stroke is a leading cause of mortality and disability, with limited treatment options due to the blood-brain barrier. Nanotechnology offers new approaches, but most research focuses on anticancer and antiviral effects. This review highlights the neuroprotective mechanisms of nanomaterials, emphasizing SeNPs, which are vital microelements involved in selenoproteins. SeNPs can cross the blood-brain barrier, regulate selenoprotein activity, and reduce oxidative stress. They enhance antioxidant enzymes, suppress pro-oxidant proteins, and modulate signaling pathways like Bcl-2 and NF-κB, reducing apoptosis. SeNPs also activate A2-reactive astrogliosis, which protects neurons. Their effects depend on size and shape, with optimal sizes (e.g., 100 nm) promoting protective gene expression. SeNPs reduce Ca²+ overload, prevent mitochondrial dysfunction, and modulate ER stress. They also enhance BDNF and GDNF, supporting neuronal survival. Acute effects include Ca²+ signaling activation in astrocytes, which may protect neurons through neuroglial interactions. SeNPs enter cells via endocytosis, activating PLC and phosphoinositide pathways. While SeNPs show potential, their long-term effects and mechanisms require further study. This review underscores the importance of understanding SeNPs' role in neuroprotection against ischemia.Selenium nanoparticles (SeNPs) show promise in protecting the brain from stroke by targeting signaling and metabolic pathways. Stroke is a leading cause of mortality and disability, with limited treatment options due to the blood-brain barrier. Nanotechnology offers new approaches, but most research focuses on anticancer and antiviral effects. This review highlights the neuroprotective mechanisms of nanomaterials, emphasizing SeNPs, which are vital microelements involved in selenoproteins. SeNPs can cross the blood-brain barrier, regulate selenoprotein activity, and reduce oxidative stress. They enhance antioxidant enzymes, suppress pro-oxidant proteins, and modulate signaling pathways like Bcl-2 and NF-κB, reducing apoptosis. SeNPs also activate A2-reactive astrogliosis, which protects neurons. Their effects depend on size and shape, with optimal sizes (e.g., 100 nm) promoting protective gene expression. SeNPs reduce Ca²+ overload, prevent mitochondrial dysfunction, and modulate ER stress. They also enhance BDNF and GDNF, supporting neuronal survival. Acute effects include Ca²+ signaling activation in astrocytes, which may protect neurons through neuroglial interactions. SeNPs enter cells via endocytosis, activating PLC and phosphoinositide pathways. While SeNPs show potential, their long-term effects and mechanisms require further study. This review underscores the importance of understanding SeNPs' role in neuroprotection against ischemia.