Melanoma is an aggressive cancer, the incidence of which is increasing worldwide. Limited therapies are currently available, particularly following metastasis. The aim of the present study was to investigate the inhibiting effect of methionine enkephalin (MENK) on human melanoma via opioid receptors. The results of the present study revealed that MENK markedly regulates the proliferation of A375 cells, causing cell cycle arrest in G0/G1 phase and a decrease in the percentage of cells in S and G2/M phases. Reverse transcription‑quantitative polymerase chain reaction demonstrated that MENK treatment increased opioid receptor expression in A375 cells. Furthermore, the expression level of survivin, an inhibitory apoptotic protein, was 1.1% of the level in the control group in the MENK group following 48 h of treatment. In conclusion, the results of the present study revealed, to the best of our knowledge for the first time, that MENK may inhibit growth and induce apoptosis of A375 cells, and describes a potential mechanism underlying these effects. Therefore, MENK should be investigated as a primary therapy for human melanoma cancer and as an adjuvant to other chemotherapies. Further studies are required to develop an optimal strategy for the use of MENK for the treatment of human cancers.