A pH/GSH dual-responsive poly(amino acid) nanogel (NG/EDA) was developed to deliver edaravone (EDA) for neuroprotection in cerebral ischemia injury. The nanogel was designed to release EDA in response to acidic and GSH-rich environments in ischemic tissues, enabling targeted and sustained drug delivery. NG/EDA exhibited a sub-spherical morphology with a hydrodynamic diameter of 112.3 ± 8.2 nm and efficiently crossed the blood-brain barrier (BBB), accumulating at the site of cerebral ischemia. In vitro and in vivo studies showed that NG/EDA significantly increased neuron survival and reduced infarct volume compared to free EDA. The nanogel inhibited ferroptosis, a type of iron-dependent cell death, by reducing lipid peroxidation, oxidative stress, and iron overload. It also enhanced the levels of glutathione (GSH), a key antioxidant, and regulated the p38/ERK MAPK signaling pathway, which is involved in iron metabolism and ferroptosis. NG/EDA demonstrated superior neuroprotection in a permanent middle cerebral artery occlusion (pMCAO) mouse model, with reduced neurological deficits and improved survival. The study highlights the potential of NG/EDA as a promising therapeutic strategy for ischemic stroke and other central nervous system diseases.A pH/GSH dual-responsive poly(amino acid) nanogel (NG/EDA) was developed to deliver edaravone (EDA) for neuroprotection in cerebral ischemia injury. The nanogel was designed to release EDA in response to acidic and GSH-rich environments in ischemic tissues, enabling targeted and sustained drug delivery. NG/EDA exhibited a sub-spherical morphology with a hydrodynamic diameter of 112.3 ± 8.2 nm and efficiently crossed the blood-brain barrier (BBB), accumulating at the site of cerebral ischemia. In vitro and in vivo studies showed that NG/EDA significantly increased neuron survival and reduced infarct volume compared to free EDA. The nanogel inhibited ferroptosis, a type of iron-dependent cell death, by reducing lipid peroxidation, oxidative stress, and iron overload. It also enhanced the levels of glutathione (GSH), a key antioxidant, and regulated the p38/ERK MAPK signaling pathway, which is involved in iron metabolism and ferroptosis. NG/EDA demonstrated superior neuroprotection in a permanent middle cerebral artery occlusion (pMCAO) mouse model, with reduced neurological deficits and improved survival. The study highlights the potential of NG/EDA as a promising therapeutic strategy for ischemic stroke and other central nervous system diseases.