A novel series of gardenamide A derivatives was synthesized as potential anti-Alzheimer's disease agents. The neuroprotective effects of these multifunctional agents against oxygen-glucose deprivation (OGD)-induced neurotoxicity in rat cortical neurons, and hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>)- and amyloid-β<sub>1-42</sub> (Aβ<sub>1-42</sub>)-induced neurotoxicity in rat hippocampal neurons were evaluated. <i>In vitro</i> studies revealed that these compounds demonstrated moderate to good multifunctional neuroprotective activity. Among the entire series, compounds <b>10e</b>, <b>10j</b>, <b>10n</b> and <b>10p</b> appeared to be the most active multifunctional neuroprotective agents. Studies indicate that compounds <b>10e</b>, <b>10f</b>, <b>10h</b>, <b>10i</b>, <b>10j</b>, <b>10n</b> and <b>10p</b> exhibit significant activities against OGD-induced neurotoxicity in rat cortical neurons, and <b>10e</b>, <b>10j</b>, <b>10n</b> and <b>10p</b> show prominent activities against H<sub>2</sub>O<sub>2</sub>- and Aβ<sub>1-42</sub>-induced neurotoxicity in rat hippocampal neurons. Moreover, these derivatives did not exert conspicuous neurotoxicity in rat cortical neurons. Thus, the present study evidently shows that <b>10e</b>, <b>10j</b>, <b>10n</b> and <b>10p</b> are potent multifunctional neuroprotective agents, which may serve as promising lead candidates for anti-Alzheimer's disease drug development.