Vascular dementia (VD) is a degenerative cerebrovascular disorder, leading to progressive decline of cognitive abilities and memory. Rehmannioside A (ReA) is isolated from Rehmanniae Radix, which exhibits protective role against various diseases. The present study was performed to calculate the possible neuroprotective effects of ReA on VD. Here, the morris water maze (MWM) test and electrophysiological recordings indicated that ReA reduced cognitive deficits. Additionally, through hematoxylin and eosin (H&E) and Nissl staining, ReA attenuated the histological alterations of hippocampus in rats with VD. ReA group significantly reduced oxidative stress, inflammatory response and apoptosis in the hippocampus of rats with VD, which was linked to the activation of nuclear erythroid related factor-2 (Nrf2), while the inactivation of nuclear factor-κB (NF-κB) and Caspase-3. Further, the anti-oxidative, anti-inflammatory and anti-apoptosis abilities of ReA were confirmed in cells stimulated by hydrogen peroxide. Overall, the results above demonstrated the protective effects of ReA against cognitive deficits and indicated the potential value of ReA in the therapy of VD in future.