Oxidative damage induced by glutamate triggers neuronal death in cerebral ischemic/reperfusion injury. BTB and CNC homology 1 (BACH1) is a major link between the cellular heme level, the redox state and the transcriptional response. p-Coumaric acid (p-CA) is a natural antioxidant that has been shown to ameliorate ischemic/reperfusion injury. In this study, we investigated whether and how p-CA regulated BACH1 in ischemic/reperfusion injury from the perspective of BACH1 subcellular localization and function. Middle cerebral artery occlusion (MCAO) model was established in male mice. MCAO mice were treated with p-CA (50, 100 mg/kg, ip) twice 5 min after MCAO and 5 h after reperfusion operation, respectively. We showed that p-CA treatment exerted dramatic neuroprotective effects, which were associated with the inhibition of BACH1. In HT22 cells, treatment with p-CA (20 μM) ameliorated OGD/R or glutamate-induced oxidative damage and mitochondrial dysfunction through decreasing the protein level of BACH1, the beneficial effect of p-CA was blocked by BACH1 overexpression. We demonstrated that BACH1 level was markedly elevated in the nucleus of HT22 cells under glutamate stimulation, and transcriptionally regulated NADPH oxidase 4 (NOX4) expression, thus mediating ROS outbreak. p-CA treatment activated the activated Cdc42-associated kinase 1 (ACK1)/protein kinase B (AKT) cascade to facilitate the phosphorylation of BACH1, augmented its interaction with chromosome region maintenance 1 (CRM1), thereby leading to the export of BACH1 from the nucleus and degradation mediated by heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1). In accord with this, administration of ACK1 inhibitor AIM-100 (20 mg/kg, ip) 5 min after MCAO significantly attenuated the neuroprotective effects of p-CA in MCAO mice. We concluded that ACK1/AKT/BACH1 axis may serve as a promising therapeutic approach for the management of ischemic stroke, thereby broadening the clinical utility of p-CA.Keywords: ischemic/reperfusion injury; p-Coumaric acid; BACH1; NOX4; ACK1/AKT; AIM-100.