Following ischemic stroke, aquaporin 4 (AQP4) expression modifications have been associated with increased inflammation. However, the underlying mechanisms are not fully understood. This study aims to elucidate the mechanistic basis of post-cerebral ischemia-reperfusion (I/R) inflammation by employing the AQP4-specific inhibitor, AER-271. The middle cerebral artery occlusion (MCAO) model was used to induce ischemic stroke in mice. C57BL/6 mice were randomly allocated into four groups: sham operation, I/R, AER-271, and 2-(nicotinamide)-1,3,4-thiadiazole (TGN-020) treatment, with observations recorded at 1 day, 3 days, and 7 days post-tMCAO. Each group consisted of 15 mice. Procedures included histological examination through HE staining, neurological scoring, Western blot analysis, and immunofluorescence staining. AER-271 treatment yielded significant improvements in post-stroke weight recovery and neurological scores, accompanied by a reduction in cerebral infarction volume. Moreover, AER-271 exhibited a noticeable influence on autophagic and apoptotic pathways, affecting the activation of both pro-inflammatory and anti-inflammatory cytokines. Alterations in the levels of inflammatory biomarkers MCP-1, NLRP3, and caspase 1 were also detected. Finally, a comparative assessment of the effects of AER-271 and TGN-020 in mitigating apoptosis and microglial polarization in ischemic mice revealed neuroprotective effects with no significant difference in efficacy. This study provides essential insights into the neuroprotective mechanisms of AER-271 in cerebral ischemia-reperfusion injury, offering potential clinical applications in the treatment of ischemic cerebrovascular disorders.