This study was initiated to isolate active metabolites from the leaves of Panax ginseng. Among them, picrionoside A, a megastigmane glucoside, was isolated from the leaves of P. ginseng C. A. MAYER and its chemical structure was determined based on spectroscopic methods, including FAB-MS, one-dimensional (1D)-NMR, 2D-NMR, and IR spectroscopy. Picrionoside A from P. ginseng has not been investigated previously, and its biological or pharmaceutical activities have not been reported elsewhere. The IC50 value of mushroom tyrosinase-inhibitory activity of picrionoside A was 9.8 µM, and the rate of inhibition of synthesized melanin content in melan-a cells was 17.1% at a concentration of 80 µM without cytotoxicity. Furthermore, picrionoside A dramatically reduced body pigmentation in the zebrafish model. Taken together, the results suggest that picrionoside A isolated from the leaves of P. ginseng may be an effective skin-whitening agent that could be a potent candidate material in the cosmetic industry.