Remote ischemic preconditioning (RIPC) is an effective regimen for neuroprotection in ischemic stroke. Exosomes are extracellular vesicles released into the blood, where they can transfer signals throughout the body. Several studies have demonstrated that RIPC leads to many changes in circulating exosomes. However, the role of RIPC-induced exosomes in neuroprotection remains to be determined. In the current study, we demonstrate that infusion of enriched plasma exosomes from RIPC-treated mice significantly attenuates infarction size in a murine model of cerebral ischemia compared to control group receiving infusion of exosomes from non-RIPC-treated mice. Further studies show that infusion of RIPC-exosomes markedly improves neurological functions. In line with the above findings, we find that the level of hypoxia inducible transcription factor (HIF)-1α is significantly higher in plasma exosomes from mice subjected to RIPC than those from control mice, which could have contributed to the RIPC-exosome-induced neuroprotection through HIF-1α-induced signals including the enhanced tolerance to hypoxia. To our knowledge, this is the first to demonstrate RIPC protects against cerebral ischemia through inducing neuroprotective exosomes.