<p>Aldose reductase (AR) is involved in the pathogenesis of ischemic stroke; however, the mechanisms are not well understood. This study aimed to evaluate the role and underlying mechanisms of AR inhibition in ischemic stroke. We found that microglial neuroinflammatory responses to oxygen glucose deprivation/reperfusion (OGD/R) were attenuated by either sorbinil-mediated AR inhibition or AR knockdown. Sorbinil (5–20 μM) attenuated OGD/R-induced endoplasmic reticulum (ER) stress and downstream c-Jun N-terminal kinase (JNK) activation in microglia. Further analysis revealed that sorbinil suppressed microglial autophagic hyperactivation, reduced nuclear receptor coactivator 4 expression, and elevated ferritin heavy chain (FTH1) levels. This effect was accompanied by diminished FTH1 colocalization with lysosomes and decreased intracellular iron (Fe²⁺) concentrations. Critically, FTH1 knockdown attenuated the inhibitory effect of sorbinil on Fe²⁺ and interlenkin-1β in microglia. Furthermore, sorbinil mitigated OGD/R-triggered oxidative stress in microglia. Moreover, sorbinil had similar effects on microglia exposed to thapsigargin-induced ER stress. Notably, the protective efficacy of sorbinil was attenuated by the pharmacological activation of JNK. In a mouse middle cerebral artery occlusion/reperfusion (MCAO/R) model, sorbinil (4, 8, and 16 mg/kg; i.p.) ameliorated neurological deficits and decreased the volume of cerebral infraction in MCAO/R model mice. This suppression coincided with attenuated neuroinflammation and the activation of ER stress and ferritinophagy in MCAO/R model mice. Overall, this study reveals a novel role of AR inhibition in regulating microglial ER stress–ferritinophagy signaling during cerebral ischemia. AR represents a promising therapeutic target for mitigating cerebral ischemia‒reperfusion injury.</p>