To investigate the antioxidant and anti-melanogenesis activities of an ultrasonic extract of red sea cucumber, Stichopus japonicus, collected from Jeju Island. Methods: Antioxidant activity experiments were assessed by an electron spin resonance system and a cellular model of immortalized human keratinocytes (HaCaT) to determine its radical scavenging activity and protective effects against 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH)-induced oxidative stress. Antimelanogenic activity of the ultrasonic extract of red sea cucumber was also examined using the melanoma cell model B16F10 and mushroom tyrosinase. Following the induction by ?-melanocytestimulating hormone, the effects of the ultrasonic extract of red sea cucumber on intracellular tyrosinase activity, melanin content and the melanogenic protein expression of microphthalmia-associated transcription factor, tyrosinase, and tyrosinase-related proteins (TRP-1, and TRP-2) were examined. Results: The ultrasonic extract of red sea cucumber significantly scavenged 2,2-diphenyl-1-picrylhydrazyl and alkyl radicals [IC50: (0.9240.035) and (0.3270.006) mg/mL, respectively], as well as showed a protective effect against oxidative stress and attenuated generation of intracellular reactive oxygen species on AAPHinduced HaCaT cells, with no cytotoxicity (12.5-400 ug/mL). The ultrasonic extract of red sea cucumber also exhibited a tyrosinase inhibitory effect [IC50: (2.7500.006) mg/mL]. On ?-melanocytestimulating hormone-stimulated B16F10 melanoma cells, the ultrasonic extract of red sea cucumber (25-200 ug/mL) significantly inhibited not only melanin synthesis and tyrosinase activity, but also protein expressions of microphthalmia-associated transcriptional factor, tyrosinase, TRP-1, and TRP-2. Conclusions: The ultrasonic extract of red sea cucumber shows antioxidant and anti-melanogenic potential and may be a natural candidate for anti-aging as well as a whitening agent in the cosmeceuticals industry.