A series of aurone Mannich base derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives were selective AChE inhibitors with good multifunctional properties. Among them, compound 7d exhibited outstanding inhibitory activity for RatAChE, EeAChE and HuAChE (IC50 = 0.00878 ± 0.0002 μM, 0.0212 ± 0.006 μM and 0.0371 ± 0.004 μM, respectively). Moreover, 7d displayed high antioxidant activity and could confer significant neuroprotective effect against H2O2-induced PC-12 cell injury. In addition, 7d also showed biometal chelating abilities, good self- and Cu2+-induced Aβ1-42 aggregation inhibitory potency and high BBB permeability. These multifunctional properties highlight 7d as promising candidate for further studies directed to the development of novel drugs against AD.