Cancer represents one of the major causes of mortality worldwide, indeed 19.3 million new cases and almost 10.0 million deaths have been estimated last year. Among the different type of cancers, malignant melanoma represents the most aggressive and deadly skin cancers. Unfortunately, the long-term efficacy of melanoma treatments is limited by the lack of clinical effects, together with the onset of side effects and resistance. The latter is a major obstacle for the success of the melanoma therapy, thus the exploration of new potent and safer anticancer agents is of great importance. Recently, numerous plant species, used for therapeutic purposes and containing various non-toxic nutraceuticals, have been widely studied. In particular, we investigated the antioxidant and anticancer properties on melanoma cells of three Annona cherimola leaves extracts (ethanolic, methanolic and aqueous). The ethanolic extract showed the most promising and interesting anticancer activity, mostly on the malignant A2058 melanoma cell line (IC₅₀ = 5.6±0.8 ng/mL), without exerting cytotoxicity on the normal cells. It was also able to block the melanoma cells migration process, modulating the expression levels of some involved proteins. In addition, the A2058 cells treated with the ethanolic extract showed a clear disorganization of cytoskeleton dynamic, inducing cell apoptosis. Finally, numerous bioactive compounds, responsible of the antioxidant and antitumoral properties, were identified in the studied extracts.