Cerebral ischemia-reperfusion injury (CIRI) is a key pathological link in the deterioration of neurological function after stroke. Its mechanism is closely related to oxidative stress and the inflammatory response,and ultimately leads to severe neuronal damage. The nuclear factor E2-related factor 2 / heme oxygenase-1 (Nrf2 / HO-1) signaling pathway, which mediates endogenous protective effects, has recently received extensive attention. This pathway plays a central role in maintaining cellular redox homeostasis by regulating antioxidant, anti-inflammatory,and anti-apoptotic processes. This review explores the activation mechanism and multi-directional protective effect of the Nrf2 / HO-1 signaling pathway in CIRI, and analyzes the therapeutic potential of targeting this pathway, to provide a theoretical basis for the development of new neuroprotective drugs to optimize clinical treatment strategies and improve the prognosis of patients with CIRI.