ABSTRACT Purpose: Stroke is an acute cerebrovascular disease. Astragaloside IV (AS-IV) is an active ingredient extracted from Astragalus membranaceus with an established therapeutic effect on central nervous system diseases. This study examined the neuroprotective properties and possible mechanisms of AS-IV in stroke-triggered early brain injury (EBI) in a rat transient middle cerebral artery occlusion (MCAO) model. Methods: The neurological scores and brain water content were analyzed. 2,3,5-triphenyl tetrazolium chloride (TTC) staining was utilized to determine the infarct volume, neuroinflammatory cytokine levels, and ferroptosis-related genes and proteins, and neuronal damage and molecular mechanisms were evaluated by terminal deoxynucleotidyl transferase dutp nick-end labeling (TUNEL) staining, western blotting, and real-time polymerase chain reaction. Results: AS-IV administration decreased the infarct volume, brain edema, neurological deficits, and inflammatory cytokines TNF-α, interleukin-1β (IL-1β), IL-6, and NF-κB, increased the levels of SLC7A11 and glutathione peroxidase 4 (GPX4), decreased lipid reactive oxygen species (ROS) levels, and prevented neuronal ferroptosis. Meanwhile, AS-IV triggered the Nrf2/HO-1 signaling pathway and alleviated ferroptosis due to the induction of stroke. Conclusions: Hence, the findings of this research illustrate that AS-IV administration can improve delayed ischemic neurological deficits and decrease neuronal death by modulating nuroinflammation and ferroptosis via the Nrf2/HO-1 signaling pathway. Purpose disease ASIV AS (AS-IV diseases stroketriggered stroke EBI (EBI MCAO (MCAO model Methods analyzed 2,3,5triphenyl 235triphenyl triphenyl 2,3,5 2 3 5 TTC (TTC volume ferroptosisrelated related proteins nickend nick end TUNEL (TUNEL blotting realtime real time reaction Results edema TNFα, TNFα TNF α, α TNF-α interleukin1β interleukinβ interleukin 1β β IL1β, IL1β ILβ IL , (IL-1β) IL6, IL6 6, 6 IL-6 NFκB, NFκB NF κB, κB NF-κB SLCA SLC A SLC7A1 GPX4, GPX4 GPX (GPX4) ROS (ROS Meanwhile Nrf2/HO1 Nrf2HO1 NrfHO Nrf2/HO 1 Nrf2 HO Nrf Nrf2/HO- Conclusions Hence 5triphenyl 235 2,3, (IL-1β IL- SLC7A (GPX4 HO1 Nrf2HO 23 2,3 (GPX 2,