BACKGROUND AND PURPOSE Neuroprotection is an important strategy for ischemic stroke treatment. Cajaninstilbene acid (CSA), a unique stilbenoid with a styryl group, is a potential neuroprotective agent. Hence, this study aimed to evaluate the neuroprotective effect and molecular mechanism of CSA against cerebral ischemia/reperfusion (I/R) damages. EXPERIMENTAL APPROACH The ischemic stroke was modeled by oxygen and glucose deprivation/reoxygenation (OGD/R) in SH-SY5Y cells and transient middle cerebral artery occlusion/reperfusion (MCAO/R) in rats. Tert-butyl hydroperoxide (t-BHP) was used to induce oxidative stress in cells. The signaling pathways were analyzed by Western blotting and inhibitor blocking. KEY RESULTS CSA possessed significant neuroprotective activity, as evidenced by the reduced cell death in OGD/R or t-BHP injured cells, and decreased infarct volume and neurological deficits in MCAO/R rats. Further studies indicated that the protective effect was achieved via the antioxidant activity of CSA, which decreased the oxidative stress and its related mitochondrial dysfunction in cells. Notably, Nrf2 was activated in cells and MCAO/R rats by CSA, and the inhibition of Nrf2 by brusatol weakened CSA-mediated neuroprotection. Furthermore, after applying a series of kinase inhibitors, CSA-induced Nrf2 activation was markedly inhibited by BML-275 (an AMPK inhibitor), implying that AMPK was the dominant kinase to regulate the Nrf2 pathway for CSA’s neuroprotective effects with enhanced AMPK phosphorylation observed both in vivo and in vitro. CONCLUSION AND IMPLICATION CSA exerted neuroprotection via activating AMPK/Nrf2 pathway to reduce I/R-induced cellular oxidative stress and mitochondrial disfunction. CSA could be a potential neuroprotective drug candidate for the treatment of ischemic stroke.