Objective To investigate the neuroprotective effect of remote ischemic preconditioning (RIPC) against hypoxic ischemia through decreased neuronal DNA methyltransferase (DNMT) levels via plasma exosomes. Methods C57BL / 6J mice were subjected to RIPC with the simultaneous tail vein injection of the exosome inhibitor GW4869; after 1 hour, middle cerebral artery occlusion (MCAO) was performed. Mice were randomized into four groups. Bederson scores and cornering tests were used to assess the degree of neurologic impairment. Expression levels of DNA methyltransferases ( DNMTs) and nerve damage-related genes in the mouse cerebral cortex were evaluated using RT-qPCR and Western blot. Plasma exosomes were extracted from mice before and after RIPC and cocultured with mouse neuronal cells (HT22) for oxygen glucose deprivation (OGD). Cell viability was assessed using CCK8 assays. The cell morphology and fluorescence intensity of the anti-apoptotic protein Bcl-2 were observed through immunofluorescence, and the mRNA and protein expression levels of DNMTs and apoptotic genes (Caspase3, BAX,and Bcl-2) were detected. Results Bederson scores and cornering experiments showed that RIPC intervention improved neurological deficits significantly after MCAO in mice, and its neuroprotective effect was significantly attenuated after the administration of GW4869(P<0. 05). RIPC treatment down-regulated DNMTs, Caspase3, and BAX and up-regulated Bcl-2 in the cerebral cortex of MCAO mice(P<0. 05). In vitro assays showed that RIPCderived exosomes reduce DNMT expression, increase the fluorescence intensity of Bcl-2, and improve cell morphology in HT22 cells under OGD conditions, while down-regulating Caspase3 and BAX and increasing cell viability ( P<0. 05). Conclusions RIPC may exert a neuroprotective effect by downregulating DNMTs in a plasma exosomemediated manner, inhibiting Caspase3 and BAX expression, increasing Bcl-2 expression, inhibiting neuronal apoptosis, and increasing the tolerance of neuronal cells to the hypoxic-ischemic environment.