Malignant melanoma, one of the most aggressive skin cancers, has a very high mortality rate. Currently, the number of drugs to treat melanoma is low. Although new immunotherapeutic approaches based on the use of antibodies against immune checkpoints have shown long term responses, it is urgent to develop novel anti-melanoma drugs with a high efficiency and a low toxicity in a large number of patients. Lycorine, a natural product, has been reported to exert antitumor effects on some cancers. However, the impact of lycorine on melanoma cells is still unknown. Using the CCK8 assay, we found that lycorine can suppress the proliferation of melanoma A375 cells in a dose-time-dependent manner. Moreover, a transwell assay showed that lycorine inhibited the migration and invasion of A375 cells significantly. Further, lycorine treatment could induce the apoptosis of the A375 cells. Biochemical analyses showed that the expression level of the anti-apoptosis Bcl-2 protein decreased, while the expression of the pro-apoptosis protein Bax and active caspase-3 increased after lycorine treatment. Finally, using western blot assay, we found that the antitumor effects of lycorine on A375 cells might be through the inactivation of the PI3K/Akt signaling pathway. Based on these observations, we suggest that lycorine may be an interesting candidate for further studies on its ability to represent a novel antitumor drug for human melanoma treatment in the future.