Resveratrol is a neutraceutical polyphenol that has been shown to improve outcome in several disease models including cancer, atherosclerosis and neurodegeneration. Resveratrol treatment prior to inducing experimental ischemic stroke results in neuroprotection reminiscent of ischemic preconditioning, a well-established mode of organ-specific tolerance to ischemia. MicroRNA are known to play a significant role in post-ischemic brain damage and plasticity. Recent studies also showed their involvement in ischemic tolerance induced by surgical preconditioning (a short duration middle cerebral artery occlusion). As resveratrol is known to be well-tolerated and easy to deliver, it is a better option than surgical preconditioning. Hence, we tested if resveratrol treatment induces changes in microRNA expression profiles with a goal to identify those microRNAs that are critical to inducing ischemic tolerance. When adult male C57BL/6J mice treated with resveratrol (10 mg/kg; i.p.) were subjected to a 1h transient middle cerebral artery occlusion after 3 days, the infarct volume (measured at 3 days of reperfusion) was significantly smaller compared to vehicle injected group (by ∼54%; p<0.05; n = 6/group). We conducted microRNA expression profiling using Affymetrix microarrays in the cerebral cortex of mice at 1 day and 3 days after resveratrol treatment in comparison to vehicle control treatment (n = 3/group). Resveratrol preconditioning altered the expression of 60 microRNAs (29 up-regulated and 31 down-regulated; by >3-fold) at both the time points studied compared to vehicle control (n =3 arrays/group). Of these, 30 were altered by >5-fold (17 up- and 13 were down-regulated). Bioinformatics analysis showed that axon guidance, transcriptional misregulation and Wnt signaling are the major biological pathways of the targets of the resveratrol-responsive microRNAs. Thus, our data shows that the ischemic tolerance afforded by resveratrol preconditioning might be mediated by microRNAs that target neuroprotective pathways.