<p>Ischemic stroke poses a significant global health challenge, resulting in severe cognitive impairments. Although thrombolytic therapy is the primary treatment, its narrow therapeutic window and risk of hemorrhagic complications limit its clinical utility. Moreover, the restoration of blood flow (reperfusion) can paradoxically exacerbate tissue damage. This process, known as ischemia/reperfusion (I/R) injury, occurs through complex pathological cascades. In this study, we evaluated the therapeutic efficacy of lemon-derived exosome-like nanovesicles (LELNs) in a rat model of global cerebral I/R injury. Male Wistar rats were divided into the following groups: Sham + PBS, I/R + PBS, I/R + Quercetin, and I/R + LELNs (10, 25, and 50 mg/kg). On day seven post-injury, behavioral assessments—including spatial memory, working memory, and anxiety-like behavior—were conducted using the Morris water maze, Y-maze, and open field tests. Based on these behavioral results, the 25 mg/kg LELNs dose was identified as optimal and selected for subsequent biochemical and molecular analyses. Our biochemical and molecular analyses assessed a comprehensive panel of parameters, including blood–brain barrier (BBB) permeability, microglial polarization (M1 and M2 phenotypes), inflammatory and anti-inflammatory cytokine profiles, oxidative stress markers (nitric oxide and superoxide dismutase), and GLT-1 expression. In summary, 25 mg/kg LELNs confer neuroprotection in cerebral I/R injury by reprogramming microglial polarization from an M1 to an M2 phenotype. This central mechanism orchestrates a protective cascade that attenuates excitotoxicity, neuroinflammation, oxidative stress, and blood–brain barrier disruption, positioning LELNs as a promising multi-targeted therapy for ischemic stroke.</p> Graphical Abstract <p></p>