This study investigated the cytotoxic effects of the synthetic cannabigerol derivative, LE-127/2, on melanoma cells and its influence on non-malignant cell lines. The findings indicated that LE-127/2 significantly suppressed melanoma cell proliferation and colony formation in a dose-dependent fashion while promoting autophagy-mediated cell death. Its reduced cytotoxicity towards non-malignant cells, in comparison to the parent compound cannabigerol (CBG), underscores its promise as a safer therapeutic alternative. Although LE-127/2 demonstrated potential anti-melanoma efficacy, the elevated IC50 values in comparison to CBG underscore the necessity for additional optimization and validation. The results endorse the advancement of LE-127/2 as a new candidate for melanoma treatment, with forthcoming research aimed at in vivo efficacy and pharmacokinetic analysis to comprehensively ascertain its therapeutic potential.