<p>Ischemic stroke (IS) induces an energy metabolism crisis, driving ischemic core and penumbra tissues toward anaerobic glycolysis and massive lactate accumulation. Initially identified as a metabolic waste, lactate is now recognized as a crucial signaling molecule. Recent studies have demonstrated that this metabolic byproduct is not merely a toxic waste product but plays a complex spatiotemporal dual role in disease progression: it may exacerbate acidosis and inflammatory damage in the early stages, while serving as an alternative energy substrate or signaling molecule with neuroprotective effects during the recovery phase. One of its core mechanisms involves novel post-translational modification-lysine lactylation (Kla). Lactate is converted into lactyl-CoA intracellularly, which specifically modifies lysine residues in histones and various functional proteins, thereby functioning as a critical “metabolic-epigenetic” sensing link to reprogram inflammatory responses, mitochondrial dynamics, and cellular fate. This article briefly reviews the mechanisms of brain metabolic disorders under normal and pathological conditions, summarizes the emerging roles of lactate, and provides new insights into lactylation-mediated neuroprotection or injury by regulating neuronal and non-neuronal cells in the ischemic microenvironment. The authors propose that future research should employ advanced methods to elucidate the detailed mechanistic connections of the “metabolic-epigenetic-immune” axis, and on this basis, develop interventions, like preconditioning strategies, targeting this axis to induce ischemic tolerance, thereby overcoming the current time window limitations in treatment and ultimately paving the way for novel therapeutic research on IS-related brain injury.</p>