A novel series of benzylisoquinoline derivatives were designed, synthesized, and evaluated as multifunctional agents against Alzheimer's disease (AD). The screening results showed that most of the compounds significantly inhibited cholinesterases (ChEs), human cholinesterases (h-ChEs) and self-induced β-amyloid (Aβ) aggregation. In particular, compound 9k showed the strongest acetylcholinesterase (AChE) inhibitory activity, being 1000-fold and 3-fold more potent than its precursor benzylisoquinoline (10) and the positive control galanthamine, respectively. In addition, 9k was a moderately potent inhibitor for h-ChEs. Compared with precursor benzylisoquinoline (36.0% at 20μМ), 9k (78.4% at 20μМ) could further inhibit Aβ aggregation. Moreover, 9k showed low cell toxicity in human SH-SY5Y neuroblastoma cells. Therefore, compound 9k might be a promising lead compound for AD treatment.