Melanoma is a malignant tumor with high metastasis and mortality. Epithelial–mesenchymal transition (EMT) was reported to be involved in the growth and metastasis of melanoma. To investigate these sections further, we showed that E26 transformation specific 1 (ETS1) could regulate growth, metastasis and EMT process of melanoma by regulating microRNA(miR)-16/SRY-related HMG box (SOX) 4 expression. MiR-16, ETS1, SOX4 and nuclear factor κB (NF-κB) expression levels in melanoma cells were examined using qPCR. ETS1, SOX4, EMT-related proteins and NF-κB signaling pathway-related proteins were examined using western blot. Cell counting kit-8 assay, transwell assay were applied to evaluate the cell proliferation, migration and invasion of melanoma cells, respectively. Besides, a dual-luciferase reporter assay was employed to verify the binding relationship between ETS1 and miR-16, miR-16 and SOX4, miR-16 and NF-κB1. We showed that ETS1 and SOX4 were upregulated in melanoma cells, while miR-16 was downregulated. MiR-16 overexpression suppressed growth, metastasis and EMT process of melanoma. We found ETS1 could bind to the promoter region of miR-16 and inhibited its transcription. ETS1 silence could inhibit growth, metastasis and EMT process of melanoma, and inhibition of miR-16 could reverse the effects. Besides, miR-16 is directly bound to SOX4 and downregulated its expression. Rescued experiments confirmed that SOX4 overexpression abolished the inhibition effect of miR-16 mimics on growth, metastasis and EMT process of melanoma. Finally, NF-κB1 as the target of miR-16 mediated downstream biological responses. ETS1 activated NF-κB signaling pathway through miR-16 via targeting SOX4, thus promoting growth, metastasis and EMT of melanoma.