The complex pathogenesis of Alzheimer's disease (AD) has become a major obstacle in its treatment. An effective approach is to develop multifunctional agents that simultaneously target multiple pathological processes. Here, a series of diosgenin-indole compounds were designed, synthesized and evaluated for their neuroprotective effects against H<sub>2</sub>O<sub>2</sub> (hydrogen peroxide), 6-OHDA (6-hydroxydopamine) and Aβ (beta amyloid) damages. Preliminary structure-activities relationship revealed that the introduction of indole fragment and electron-donating group at C-5 on ring indole could be beneficial for neuroprotective activities. Results indicated that compound 5b was the most promising candidate against cellular damage induced by H<sub>2</sub>O<sub>2</sub> (52.9 ± 1.9%), 6-OHDA (38.4 ± 2.4%) and Aβ<sub>1-42</sub> (54.4 ± 2.7%). Molecular docking study suggested the affinity for 5b bound to Aβ<sub>1-42</sub> was -40.59 kcal/mol, which revealed the strong binding affinity of 5b to Aβ<sub>1-42</sub>. The predicted values of brain/blood partition coefficient (-0.733) and polar surface area (85.118 Å<sup>2</sup>) indicated the favorable abilities of BBB permeation and absorption of 5b. In addition, 5b significantly decreased ROS (reactive oxygen species) production induced by H<sub>2</sub>O<sub>2</sub>. In the following in vivo experiment, 5b obviously attenuated memory and learning impairments of Aβ-injected mice. In summary, compound 5b could be considered as a promising dual-functional neuroprotective agent against AD.