Spinal cord ischemia-reperfusion injury (SCII) ranks as the common complication after aortic surgery, usually leading to devastating post-operative paraplegia. Microglia over-activation and neuronal cell loss are key pathological features of SCII. Curcumin is involved in several I/R injuries. However, its underlying mechanism in SCII remains elusive. Here, curcumin attenuated oxygen and glucose deprivation/reoxygenation (OGD/R)-induced oxidative injury in PC12 neuronal cells by increasing cell viability, inhibiting cell apoptosis, lactate dehydrogenase, malondialdehyde levels, but elevating anti-oxidative superoxide dismutase and glutathione peroxidase levels. Furthermore, curcumin restrained OGD/R-evoked microglia M1 activation by decreasing microglia M1 polarization marker IBA-1 and iNOS transcripts. Moreover, the increased inflammatory cytokine levels of TNF-α and IL-6 in microglia under OGD/R conditions were suppressed after curcumin treatment. Importantly, neuronal cells incubated with a conditioned medium from OGD/R-treated microglia exhibited lower cell viability and higher apoptotic ratio, which were overturned when microglia were treated with curcumin. Intriguingly, curcumin could inhibit the activation of the NF-κB pathway by Nrf2 enhancement in OGD/R-treated PC12 cells and microglia. Notably, targeting Nrf2 signaling reversed the protective efficacy of curcumin against OGD/R-evoked oxidative insult in neuronal, microglia M1 activation, inflammatory response, and microglial activation-evoked neuronal death. In vivo, curcumin improved histopathologic injury and neurologic motor function in SCII rats and attenuated oxidative stress, microglia activation and neuroinflammation in spinal cord tissues, and activation of the Nrf2/NF-κB pathway. Thus, curcumin may alleviate SCII by mitigating I/R-evoked oxidative injury in neuron and microglia activation-induced neuroinflammation and neuron death through Nrf2/NF-κB signaling, supporting a promising therapeutic agent for SCII.