Background: Alzheimer's disease (AD) is an age-related neurodegenerative disease, which manifests primarily as memory impairment accompanied by a gradual decline in cognitive function. Rehmanniae Radix Praeparata (RRP) is a traditional Chinese medicine herb, which is widely used clinically and has diverse pharmacological properties. However, the protective properties and the underlying mechanisms by which RRP counteracts oxidative stress to treat AD have not been elucidated. Methods: In the study, we explored the neuroprotective impact of RRP on mitigating oxidative stress damage using C. elegans and A beta 1-42-induced HT22 cells. In the study encompassing the use of HT22 cells, we detected cell viability, ROS level, MDA/T-AOC/CAT/SOD activity, HT22 cells apoptosis and Nrf2 translocation. Western blot analysis was used to examine changes in protein expression levels. In nematode experiments, we performed spawning assay, life-span assay, ROS level, MDA/T-AOC/CAT/SOD activity, chemotaxis assay, paralysis, serotonin sensitivity, Th S Staining, acridine orange assay, SKN-1 nuclear localization and the gst-4 expression. Results: Pretreatment of RRP significantly reduced the generation of ROS and MDA in A beta 1-42-induced HT22 cells, and increase the T -AOC, CAT and total SOD activity. RRP mitigated the toxic effect and apoptosis induced by A beta 1- 42 treatment, as evident by reduced cytochrome C release and decreased ratio of cleaved caspase-9/caspase-9, BAX/Bcl-2 and cleaved caspase-3/caspase-3. Additionally, RRP was found to induce Nrf2 nuclear translocation, elevate the expression of Nrf2 protein in the nucleus, and promote the expression of NQO1 and HO -1 proteins. In terms of the nematode experiments, RRP could prolong the survival time of N2 nematodes and improve the resistance of nematodes to external stress. RRP improved chemotaxis to chemical substances and decreased the sensitivity to 5-HT was observed in the CL2355 nematodes. It also alleviated the paralysis process and reduce A beta deposition in the pharynx of the CL4176 nematodes. RRP inhibited the production of ROS and MDA, and increased the activity of T -AOC, CAT and total SOD in the nematodes. RRP decreased apoptosis in N2 C. elegans. Together, the data demonstrated that RRP possesses antioxidant capacity by promoting SKN-1 nuclear translocation and GST-4 expression in C. elegans. Conclusion: Overall, our study suggested that the antioxidant effect of RRP might occur by regulation of Nrf2/ ARE pathway in HT22 cells, and is relevant to the activation of SKN-1 in C. elegans.