The first systematic direct diversification of a complex natural product by metal-catalyzed N-H functionalization was carried out. A new series of <i>N</i>-(hetero)aryl analogues (<b>1</b>-<b>32</b>) of the natural anti-Alzheimer's disease drug huperzine A (HPA) was prepared via palladium-catalyzed Buchwald-Hartwig cross-coupling reactions of HPA with various aryl bromides in good yields. Most of the <i>N</i>-aryl-huperzine A (<i>N</i>-aryl-HPA) analogues showed good acetylcholinesterase (AChE) inhibitory activity in <i>in vitro</i> experiments. Three arylated huperzine A analogues (<b>14</b>, <b>19</b>, and <b>30</b>) exhibited stronger anti-AChE activity than HPA. The 5-methoxy-2-pyridyl analogue (<b>30</b>) displayed the most potent AChE inhibition activity, with an IC<sub>50</sub> value of 1.5 μM, which was 7.6-fold more active than HPA. Compound <b>30</b> also exhibited better neuroprotective activity for H<sub>2</sub>O<sub>2</sub>-induced damage in SH-SY5Y cells than HPA. Structure-activity relationship analysis suggested that the electron density of the installed aromatic ring or heteroaromatic ring played a significant role in inducing the AChE inhibition activity. Overall, compound <b>30</b> showed the advantages of easy synthesis, high potency and selectivity, and improved neuroprotection, making it a potential huperzine-type lead compound for Alzheimer's disease drug development.