It has been increasingly recognized that microRNAs (miRNAs) are often dysregulated in various human malignancies and can function as oncogenes or tumor-suppressors. However, the potential roles of miRNAs and components of the miRNA biogenesis pathway remain poorly defined in melanoma. Here, we systematically profiled miRNA expression in human melanocytes and melanoma cells, and identified a prominent function of miR-125a-5p in suppressing melanoma growth. Mechanistically, we discovered that Lin28B, a well-characterized inhibitor of let-7 miRNA biogenesis, was a direct target of miR-125a-5p in melanoma. We showed that the Lin28B was aberrantly expressed in a large proportion of melanoma patients and was functionally required for melanoma progression. We further demonstrated the involvement of let-7-dependent mechanism downstream of Lin28B, resulting in the activation of transforming growth factor-β signaling cascade. Collectively, our data implicate Lin28B as a novel oncogene in melanomagenesis by mediating a miRNA regulatory circuit.