Abstract: Mitochondrial dysfunction and oxidative stress play a crucial role in the pathogenesis of Alzheimer’s disease (AD). The neuroprotective effects of the diosgenin derivative ML5 were investigated in vitro and in vivo, and the underlying mechanisms were explored. The results showed that ML5 ameliorated the study and cognitive deficits in beta-amyloid (Aβ_1-42)-induced mouse model and protected neurons in the hippocampal region. In addition, ML5 attenuated H₂O₂-induced damage to SH-SY5Y cells and increased mitochondrial membrane potential and ATP levels. Western blot and immunofluorescence results showed that ML5 activated nuclear factor-erythroid-2-related factor 2 (NRF2) signaling pathway and increased the expression of NRF2, heme oxygenase-1 (HO-1), and NAD(P)H:quinone oxidoreductase-1 (NQO-1). Our findings suggest that ML5 may be used as a therapeutic drug for AD treatment via targeting the NRF2 pathway, thereby exerting antioxidant and neuroprotective effects.