[Display omitted] • The twin Drug of diosgenin derivatives were designed and synthesized. • Compound ML5 showed excellent protection in oxygen-glucose deprivation (OGD) cells. • Compound ML5 showed appropriate inhibition of cholinesterases (ChEs) in vivo. • Compound ML5 promoted the nuclear translocation of Nrf2 and showed strong antioxidant capacity. • Compound ML5 has significant neuroprotective effect in bilateral common carotid artery occlusion (BCCAO) rats by activation of Nrf2 and inhibition of ChEs. A novel series of multitargeted molecules were designed and synthesized by combining the pharmacological role of cholinesterase inhibitor and antioxidant of steroid as potential ligands for the treatment of Vascular Dementia (VD). The oxygen-glucose deprivation (OGD) model was used to evaluate these molecules, among which the most potent compound ML5 showed the highest activity. Firstly, ML5 showed appropriate inhibition of cholinesterases (ChEs) at orally 15 mg/kg in vivo. The further test revealed that ML5 promoted the nuclear translocation of Nrf2. Furthermore, ML5 has significant neuroprotective effect in vivo model of bilateral common carotid artery occlusion (BCCAO), significantly increasing the expression of Nrf2 protein in the cerebral cortex. In the molecular docking research, we predicted the ML5 combined with hAChE and Keap1. Finally, compound ML5 displayed normal oral absorption and it was nontoxic at 500 mg/kg, po, dose. We can draw the conclusion that ML5 could be considered as a new potential compound for VD treatment. [ABSTRACT FROM AUTHOR]