We previously reported reduced expression of Sox4 in metastatic melanoma and its role in suppression of cell migration and invasion through inhibition of nuclear factor (NF)-κB p50. Sox4 can also bind to the promoter sequence of Dicer, a microRNA (miRNA) biogenesis factor. Interestingly, altered expression of Dicer was also observed in cancers. However, the potential mechanisms that regulate Dicer expression and its potential significance in melanoma progression are unknown. Here, we studied the regulation of Dicer expression by Sox4 and its role in suppression of melanoma invasion. Our data showed that Sox4 positively regulates Dicer expression by binding to its promoter sequences and enhancing its activity. We found that knockdown of Dicer enhances the matrigel invasion of melanoma cells by at least twofold. In addition, we revealed that overexpression of exogenous Dicer reverts the enhanced melanoma cell invasion upon Sox4 knockdown. Furthermore, we examined the expression of Dicer protein in a large set of melanocytic lesions (n=514) at different stages by tissue microarray and found that Dicer expression is inversely correlated with melanoma progression (P<0.0001). Consistently, reduced Dicer expression was correlated with a poorer overall and disease-specific 5-year survival of patients (P=0.015 and 0.0029, respectively). In addition, we found a significant correlation between expression of Sox4 and Dicer proteins in melanoma biopsies (P=0.009), further indicating the regulation of Dicer expression by Sox4. Finally, we revealed that knockdown of Sox4 induces a major change in the expression pattern of miRNAs in melanoma cells, mainly due to reduced expression of Dicer. Our results pinpoint the regulation of Dicer expression by Sox4 in melanoma and the critical role of Dicer in suppression of melanoma invasion. Our findings on Sox4-regulated miRNA biogenesis pathway may aid toward the development of novel targeted therapeutic approaches for melanoma.