Ischemia-reperfusion (IR) causes a wide range of irreversible injuries. Cerebral IR injury (IRI) refers to further brain tissue damage after regaining blood flow following cerebral ischemia. Methods to treat IRI are still far from being established. Oxidative stress is one of the main mechanisms of IRI initializing, and considered as an essential entry point of the treatment of IRI. Urolithin B (UB, 3-Hydroxy-6H-dibenzo[b,d]pyran-6-one) is a metabolite of ellagitannins, which are antioxidant polyphenols and has been found to be protective against oxidative stress in a variety of diseases. It is unclear how UB affects cerebral IRI, however. In our present study, using a neurological deficit score, we found that UB could suppress IR-induced neurological functional damage. 2,3,5-triphenyltetrazolium chloride (TTC) staining and neuron nissl staining showed that cerebral infarction was improved after administration of UB. Terminal deoxynucleotidyl transferase-mediated dNTP nick end labeling (TUNEL) assay and Caspase-3 measurement indicated that UB inhibited neuronal apoptosis. The oxidative stress level, reduced by UB, was analyzed by malondialdehyde (MDA) concentration and the activity of superoxide dismutase (SOD), and immunohistochemistry of inducible nitric oxide synthase (iNOS) and 8-hydroxyl-2’-deoxyguanosine (8-OHdG). Mechanically, UB stimulated Nrf2/HO-1signaling pathway. The injection of ATRA, an Nrf2 inhibitor, significantly reduced UB's neuroprotective effects mentioned above. To sum up, UB inhibits oxidative stress caused by IR through activating the Nrf2/HO-1 signaling pathway, and could potentially be used for the treatment of IRI.