In current work, we investigated the in-vitro efficacy of Caffeic acid Phenethyl Ester (CAPE) as an anti-melanoma agent in five melanoma cell lines B16-F0, B16F10, SK-MEL-28, SK-MEL-5, and MeWo and in-vivo efficacy study in skin B16-F0 melanoma tumor model in C57BL/6 mice. The IC(50) (48 h) of CAPE in above five melanoma cell lines was 15 µM. CAPE (20-200 µM) led to intracellular GSH depletion of 16-54%, and 10-25 fold increase in Reactive Oxygen Species (ROS) formation in B16-F0 cells. CAPE (15-30 µM) caused 5-7 fold increase in apoptosis in B16-F0 cells. CAPE (10, 20 and 30 mg/Kg/day) led to tumor size growth inhibition by 39 ± 33%, 54 ± 36%, and 57 ± 18%, respectively. The respective therapies led to plasma Alanine Amino Transferase (ALT) levels corresponding to 85 ± 18, 107 ± 26, 154 ± 35 IU/L in comparison to controls 66 ± 14 IU/L. At corresponding doses, the lipid peroxidation levels as measured by malondialdehyde (MDA) formation in liver homogenates were 255 ± 8 μM, 304 ± 21 μM, and 342 ± 14 μM in comparison to 208 ± 6 μM in controls. The level of MDA in kidney homogenates was 263 ± 21 μM, 282 ± 18 μM, and 350 ± 28 μM, respectively, in comparison to 212 ± 8 μM in controls. Administration of CAPE (10, 20, 30 mg/Kg/day) diminished free thiol contents in liver for 21 ± 15%, 40 ± 17%, and 44 ± 19% and in kidney homogenates for 25 ± 15%, 37 ± 18%, and 40 ± 22%, respectively, as compared to controls. Our study suggests that CAPE at 10 mg/Kg/day has significant anti-melanoma efficacy with minimal toxicity.