Increasing evidence indicates that a healthy diet plays a protective role against ischemic stroke injury. As an antioxidant food, grape powder (GP) has been shown to have a neuroprotective function after ischemic injury. In the current research, we aimed to determine whether regular GP feeding before brain damage plays a protective role against ischemic damage and its potential mechanism. Mice had GP in drinking water (DW) for 4 weeks. Then, fecal samples were collected for 16S rRNA analysis and metabolite profiling. Ischemic stroke was triggered using GP prefeed mice by middle cerebral artery occlusion (MCAo) to compare the stroke-induced infarction size to the DW group. The data showed that 4 weeks of GP pretreatment significantly decreased the ischemic infarct size. Meanwhile, GP treatment altered the gut microbiota by enriching the population of Lachnospiraceae and enhancing a gut metabolite called fiestin, which belongs to the flavonoid group. Mechanistically, we demonstrated that fiestin could inhibit LPS-induced proinflammatory macrophage polarization in vitro. We also showed that regular GP feed could decrease stroke-induced neuroinflammation in vivo. In conclusion, our study demonstrated that 4 weeks of GP feeding attenuates experimental ischemic stroke via the gut-brain-immune axis.