Background <p>Ischemic stroke is a leading cause of mortality and long-term disability. Current reperfusion therapies are constrained by narrow treatment windows and risk of complications. This systematic preclinical review aimed to analyze the effects and mechanisms of electroacupuncture (EA) at Neiguan (PC6) in the middle cerebral artery occlusion (MCAO) animal models of ischemic stroke.</p> Methods <p>A total of 23 preclinical studies using MCAO models were included. The analyses focused on neurological functional recovery, infarct volume, and mechanistic pathways affected by EA at PC6.</p> Results <p>EA at PC6 significantly improved neurological outcomes and reduced infarct volumes in experimental stroke models. The neuroprotective mechanisms involved suppression of innate immune activation, reduction of pro-inflammatory cytokines, and activation of endogenous antioxidant systems, mitigating oxidative stress. Additionally, EA modulated iron metabolism to inhibit ferroptosis and promoted neuroplasticity by upregulating brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and molecular markers of axonal and synaptic remodeling. EA also preserved blood–brain barrier integrity by maintaining tight junction proteins and inhibiting matrix metalloproteinase-9 (MMP-9), thereby reducing cerebral edema and vascular permeability.</p> Conclusions <p>EA at PC6 demonstrates multi-modal neuroprotective effects via anti-inflammatory, antioxidant, neurotrophic, and vascular-stabilizing mechanisms in preclinical ischemic stroke models. Further clinical research is warranted to validate its therapeutic potential in human stroke recovery.</p> Graphical abstract <p></p>