Cumulative evidence suggests that β-amyloid and oxidative stress are closely related with each other and play key roles in the process of Alzheimer's disease (AD). Multitarget regulation of both pathways might represent a promising therapeutic strategy. Here, a series of selenium-containing compounds based on ebselen and verubecestat were designed and synthesized. Biological evaluation showed that 13f exhibited good BACE-1 inhibitory activity (IC<sub>50</sub> = 1.06 μΜ) and potent GPx-like activity (ν<sub>0</sub> = 183.0 μM min<sup>-1</sup>). Aβ production experiment indicated that 13f could reduce the secretion of Aβ1-40 in HEK APPswe 293T cells. Moreover, 13f exerted a cytoprotective effect against the H<sub>2</sub>O<sub>2</sub> or 6-OHDA caused cell damage via alleviation of intracellular ROS, mitochondrial dysfunction, Ca<sup>2+</sup> overload and cell apoptosis. The mechanism studies indicated that 13f exhibited cytoprotective effect by activating the Keap1-Nrf2-ARE pathway and stimulating downstream anti-oxidant protein including HO-1, NQO1, TrxR1, GCLC, and GCLM. In addition, 13f significantly reduced the production of NO and IL-6 induced by LPS in BV2 cells, which confirmed its anti-inflammatory activity as a Nrf2 activator. The BBB permeation assay predicted that 13f was able to cross the BBB. In summary, 13f might be a promising multi-target-directed ligand for the treatment of AD.