Nodal, an important embryonic morphogen, has been reported to function in tumorigenesis. Here we report for the first time that Nodal promotes malignancy by inducing epithelial–mesenchymal transition (EMT) in B16 murine melanoma. These cells displayed increased migration and invasion abilities upon treating with Nodal, accompanying with typical phenotype changes of EMT. In contrast, Nodal knockdown or blocking Nodal signaling using a specific antagonist SB431542 repressed the EMT phenotype as well as reduced cell motility and invasiveness. Treatment with Nodal also induced expression of transcription factor Snail. Snail knockdown abolished the Nodal-induced EMT in B16 cells. We further show that Snail expression is mediated by the Nodal-regulated AKT/GSK-3β signaling. Taken together, these results revealed that Nodal promotes the aggressive phenotype of B16 murine melanoma cells by inducing EMT via up-regulation of Snail. This study provides a better understanding of Nodal function in melanoma, and suggests a potential novel target for clinical therapeutic research.