The core therapeutic goal of acute ischemic stroke is to salvage the ischemic penumbra. Although reperfusion therapy restores cerebral blood flow, the phenomenon of "futile recanalization" remains common, indicating that vascular recanalization alone cannot fully prevent ischemia-reperfusion brain injury. As an essential complementary strategy to reperfusion, brain cytoprotection therapy aims to mitigate reperfusion-related damage and enhance neurological recovery through multi-target interventions. This review summarizes recent advances in combined reperfusion and brain cytoprotection therapy for acute ischemic stroke based on high-quality clinical evidence, focusing on the latest findings and clinical applicability of pharmacological and non-pharmacological protective strategies. It also discusses the potential role and prospects of integrated multi-phase interventions in improving neurological outcomes, offering insights for optimizing brain cytoprotection strategies following reperfusion therapy in acute ischemic stroke.