Background <p>Melanoma is one of the most aggressive forms of cancer in human due to its ability to invade tissues and metastasize. The aim of this work is to examine the effect of our patented compound <i>Prunus spinosa</i> Trigno + Nutraceutical Activator Complex (PsT + NAC^®) on primary (WM115), metastatic (WM266-4), and malignant (A375) human melanoma cell lines.</p> Methods and Results <p>The data show that PsT + NAC^® induced a dose- and time-dependent reduction in cell viability in all melanoma cell lines, particularly in the metastatic WM266-4. Persistent morphological changes indicative of cell death were observed, which remained irreversible even after the cells recovered from treatment. The treatment with PsT + NAC^® altered cell migration and motility by remodeling of actin cytoskeleton. Cell cycle analysis revealed a G2/M phase arrest in the primary WM115 cells, and a G1 phase arrest—at lower concentrations—in the metastatic WM266-4 cells, and in the malignant A375 cells. As the treatment concentration increased, all melanoma cell lines showed an increase in the sub-G1 population, associated with apoptosis. Western blotting analysis revealed that lower concentrations of PsT + NAC^® induced a protective autophagic response, while higher concentrations triggered caspase-dependent apoptosis.</p> Conclusion <p>These results demonstrate the efficacy of PsT + NAC^® in inhibiting the growth of BRAF-mutant melanoma cells.</p>