Melanoma, an aggressive form of skin cancer, can be fatal if not diagnosed and treated early. Melanoma is widely recognized to resist advanced cancer treatments, including immune checkpoint inhibitors, kinase inhibitors, and chemotherapy. Numerous studies have shown that various Cannabis sativa extracts exhibit potential anticancer effects against different types of tumours both in vitro and in vivo. This study is the first to report that PHEC-66, a Cannabis sativa extract, displays antiproliferative effects against MM418-C1, MM329 and MM96L melanoma cells. Although these findings suggest that PHEC-66 has promising potential as a pharmacotherapeutic agent for melanoma treatment, further research is necessary to evaluate its safety, efficacy, and clinical applications.