A novel series of tetrahydroisoquinoline-benzimidazole hybrids have been designed and synthesized as multifunctional agents against Alzheimer's disease (AD). These compounds were evaluated for their inhibition of neuroinflammation and human β-secretase (hBACE1), and neuroprotective activity. Among them, compound BD3 possessed significant anti-neuroinflammatory activity (IC<sub>50</sub> = 5.07 μM against nitric oxide production) through inhibiting the expression and secretion of proinflammatory cytokines in BV2 cells. Compound BD3 also exhibited moderate hBACE1 inhibitory activity (65.7% inhibition at 20 μM) and potent neuroprotective effect by increasing GSH level and reducing ROS production (91.8% cell viability at 5 μM). Parallel artificial membrane permeation assay demonstrated that BD3 could cross the blood-brain barrier (BBB). Thus, this study demonstrates that the compounds with tetrahydroisoquinoline-benzimidazole scaffold are potential anti-AD agents, and they are worth for the further development.