This study developed a pH/GSH dual-responsive poly(amino acid) nanogel (NG/EDA) to improve the neuroprotective efficacy of edaravone (EDA) in cerebral ischemic injury. The nanogel was designed to be triggered by acidic and EDA-induced high-level glutathione (GSH) microenvironments, enabling selective and sustained EDA release at the site of ischemic injury. NG/EDA exhibited a uniform sub-spherical morphology with a mean hydrodynamic diameter of 112.3 ± 8.2 nm and efficiently accumulated at the ischemic injury site in pMCAO mice, demonstrating enhanced BBB crossing. Notably, 50 μM EDA in NG/EDA significantly increased neuron survival (29.3%) following oxygen and glucose deprivation by inhibiting ferroptosis. Administration of NG/EDA for 7 days reduced infarct volume to 22.2% ± 7.2% and decreased neurobehavioral scores from 9.0 ± 0.6 to 2.0 ± 0.8. The pH/GSH dual-responsive nanoplatform shows promise as a unique and promising modality for neuroprotection in ischemic stroke and other central nervous system diseases.This study developed a pH/GSH dual-responsive poly(amino acid) nanogel (NG/EDA) to improve the neuroprotective efficacy of edaravone (EDA) in cerebral ischemic injury. The nanogel was designed to be triggered by acidic and EDA-induced high-level glutathione (GSH) microenvironments, enabling selective and sustained EDA release at the site of ischemic injury. NG/EDA exhibited a uniform sub-spherical morphology with a mean hydrodynamic diameter of 112.3 ± 8.2 nm and efficiently accumulated at the ischemic injury site in pMCAO mice, demonstrating enhanced BBB crossing. Notably, 50 μM EDA in NG/EDA significantly increased neuron survival (29.3%) following oxygen and glucose deprivation by inhibiting ferroptosis. Administration of NG/EDA for 7 days reduced infarct volume to 22.2% ± 7.2% and decreased neurobehavioral scores from 9.0 ± 0.6 to 2.0 ± 0.8. The pH/GSH dual-responsive nanoplatform shows promise as a unique and promising modality for neuroprotection in ischemic stroke and other central nervous system diseases.