Many natural products that inhibit melanogenesis, freckles, and hyperpigmentation have been selectively used in cosmetics because melanogenesis is linked to the multiple biogenesis cascades of melanin synthesis. However, some of these compounds have side effects that may result in their restriction in the future. We report here the isolation and structural elucidation of compounds extracted from Mansonia gagei and evaluate their activity on melanogenesis inhibition. We isolated five known compounds from M. gagei and identified them as mansonone E (1), mansorin I (2), populene F (3), mansonone G (4), and mansorin B (5). After evaluating the five compounds for cytotoxicity against B16 cells and inhibitory activity on α-melanocyte-stimulating hormone (α-MSH) induced melanogenesis, we determined that the cytotoxicity and melanogenesis-inhibitory effect of 1 were relatively low and high, respectively. Next, the effect of 1 on the expression of melanogenesis-related proteins was assessed; it was confirmed that 1 dose-dependently inhibited the expression levels of tyrosinase, tyrosinase-related protein 1 (TRP-1), TRP-2, cAMP response element binding protein (CREB), and microphthalmia-associated transcription factor (MITF) which were increased after stimulation by α-MSH. Furthermore, the effects of 1 on the phosphorylation levels of intracellular signaling pathway-related proteins were evaluated, and it was found that 1 dose-dependently rescued the phosphorylation of Akt and p38 mitogen-activated protein kinases (MAPK), which were up- or down-regulated after stimulation by α-MSH. In contrast, treatment with the phosphoinositide 3-kinase (PI3K)/Akt inhibitor wortmannin enhanced melanogenesis inhibition by mansonone E. Cumulatively, the data suggest that 1 suppresses α-MSH-induced melanogenesis in B16 cells by inhibiting both phosphorylation in the PI3K/Akt pathway and the expression of melanogenesis-related proteins.