Our previous study demonstrated that paeoveitol D, a benzofuran compound isolated from <i>Paeonia veitchii</i>, displayed activity on MT<sub>1</sub> and MT<sub>2</sub> receptors with agonistic ratios of 57.5% and 51.6% at a concentration of 1 mM. To explore the structure-activity relationships, 34 paeoveitol D derivatives were synthesized and evaluated for their MT<sub>1</sub> and MT<sub>2</sub> agonistic activities using the Fluo-8 calcium assay. Among them, 16 and 18 derivatives increased agonistic activities on the MT<sub>1</sub> and MT<sub>2</sub> receptors, respectively. Compound 18 indicated EC<sub>50</sub> values of 21.0 and 298.9 μM on MT<sub>1</sub> and MT<sub>2</sub> receptors in agonistic dose response curves with Tango assays and shortened immobility time in the forced swim test. The preliminary mechanism-of-action investigation manifested that the antidepressant activity of compound 18 may be mediated by promoting serotonin (5-HT) and dopamine (DA) levels in the mice brain. Compound 18 also showed favorable pharmacokinetic profiles and low toxicity <i>in vivo</i>. These results suggest that compound 18 could be a potential antidepressant agent.