Melanoma is a very aggressive skin cancer; its treatment bears great challenges, hence the interest in new therapeutic approaches is growing. In this review, potential nano-formulated natural drugs from plants such as Ginseng, Pistacia lentiscus, Amaranthus hypochondriacus, and Cannabis sativa in the treatment of melanoma are discussed. We discuss various characteristics of nanoformulations, including liposomes and nanoemulsions, with respect to their ability in enhancing drug delivery and bioavailability. Key mechanisms of action including reactive oxygen species modulation, apoptotic signaling induction, immune modulation through TLR4/MyD88, and inhibition of angiogenesis by VEGF pathways are discussed. Although these natural nanoformulations show promise in improving therapeutic outcomes, challenges related to their clinical application and safety persist. Further research is warranted to fully explore how this novel approach can best be utilized against melanoma.