In this study, we evaluated the effects of Korean mistletoe (Viscum album L. var. coloratum) coated with a biodegradable polymer (Eudragit(®)) wall on the growth of mouse melanoma in vivo. Oral administration of 4% (430 mg/kg/day) enteric-coated mistletoe resulted in a significant reduction in tumor volume on day 14 compared to the negative control group in B16F10 melanoma-inoculated BDF1 mice. When we measured the survival rate, enteric-coated mistletoe-received mice had a higher survival rate after day 12. Also, we investigated the mechanism involving the cancer cell growth inhibition when melanoma cells were treated with Korean mistletoe lectin (Viscum album L. var. coloratum agglutinin, VCA) and its extract in vitro. As a result, a significant G0/G1 arrest was observed in both B16BL6 and B16F10 melanoma cells with VCA or mistletoe extract. In addition, VCA or mistletoe extract induced an increase in both early and late apoptosis in cells. When we studied the molecular mechanism, our results showed that VCA and mistletoe extract can increase activated multiple caspases (caspase-1, 3, 4, 5, 6, 7, 8, and 9), dose-dependently. We also found out that VCA and mistletoe treatment causes a significant decrease in the expression of procaspase-3 and 8.