MacroH2A is the most frequently altered histone, which participates in cancer progression. Increasing evidence demonstrates that cancer progression could be regulated by macroH2A by affecting the cell cycle. In the present study, it was demonstrated that macroH2A suppresses melanoma cell progression and the molecular mechanisms underlying this process were examined. The interference and overexpression vectors of macroH2A were constructed and then transferred into B16 melanoma cells and, following transfection, were analyzed by quantitative polymerase chain reaction (PCR), western blot analysis and immunofluorescence assays. Apoptosis and the cell cycle stage among all the treatment groups were detected. Then, cyclin D1, cyclin D3, cyclin-dependent protein kinase (CDK) 4, CDK6 and CDK8 expression was detected in order to elucidate the effects of macroH2A on cell cycle-related genes. The results demonstrated that the overexpression of macroH2A suppressed melanoma cell progression and arrested the cells in the G2/M stage. Furthermore, macroH2A inhibits cyclin D1, cyclin D2, CDK6 and CDK8 expression in B16 melanoma cells. In conclusion, the results demonstrated that macroH2A, a critical component of chromatin, suppresses the development of melanoma (which results from a disordered cell cycle) through regulating cyclin D1, cyclin D3 and CDK6 genes.