<p>Alleviating cerebral ischemia-reperfusion injury (CIRI) is a crucial link in improving the prognosis of patients with acute ischemic stroke (AIS). Currently, although intra-arterial selective cooling saline infusion (IA-SCSI) can mitigate this injury to a certain extent, its therapeutic effect is limited and difficult to meet clinical needs. Our previous studies have confirmed that human serum albumin (HSA) exerts definite neuroprotective effects. However, as a macromolecular colloidal solution, elderly patients with cardiopulmonary insufficiency can only tolerate low-dose administration, a limitation that directly hinders its efficacy and clinical translation. Intra-arterial selective drug delivery enables targeted delivery of drugs to injured sites, with an effective dose significantly lower than conventional intravenous administration, which can enhance local drug concentration while reducing the risk of systemic adverse reactions. Based on this, the present study focuses on the intra-arterial selective cooling HSA infusion (IA-SCAI) regimen, aiming to systematically explore its neuroprotective effects and provide new ideas for optimizing the treatment strategy of AIS. Using the rat middle cerebral artery occlusion (MCAO) model as the research object, an IA-SCAI intervention regimen was established to systematically investigate the effects of this regimen on neurological function and related mechanisms in rats after cerebral ischemia-reperfusion. Compared with IA-SCSI, intra-arterial selective saline infusion (IA-SSI) and intra-arterial selective albumin infusion (IA-SAI), IA-SCAI exhibited superior neuroprotective effects: it not only significantly alleviated the neuroinflammatory response induced by cerebral ischemia-reperfusion injury but also effectively improved the long-term neurological function recovery of rats. Further mechanistic studies revealed that this intervention regimen can reduce blood-brain barrier (BBB) injury by inhibiting the abnormal activation of the ROCK1/MLC pathway and decreasing the expression of F-actin, which may be one of the core mechanisms underlying its neuroprotective effects. HSA represents an ideal perfusate for intra-arterial selective cooling infusion, as it alleviates CIRI by inhibiting the activation of the ROCK1/MLC pathway, reducing F-actin expression to mitigate BBB damage, and suppressing neuroinflammatory responses, thereby providing a new and effective strategy for the clinical treatment of AIS.</p>