The Sox4 transcription factor is involved in various cellular processes, such as embryonic development and differentiation. Deregulated expression of Sox4 in several human cancers has been reported to date, but its role in melanoma is unknown. We explored the role of Sox4 in melanoma pathogenesis in vivo and in vitro. Using tissue microarray, we evaluated Sox4 expression in 180 melanocytic lesions and investigated its role in melanoma cell migration and invasion. Sox4 expression was remarkably reduced in metastatic melanoma compared with dysplastic nevi (P < 0.05) and primary melanoma (P < 0.01). This reduction was correlated with a poorer disease-specific survival of melanoma patients (P = 0.039). Multivariate Cox regression analysis revealed that reduced Sox4 expression is an independent prognostic factor (P = 0.049). Knockdown of Sox4 enhanced melanoma cell invasion, migration, and stress fiber formation. The increased migration and invasion on Sox4 knockdown depends on the presence of nuclear factor (NF)-κB p50 and is abrogated when p50 is knocked down. We further observed inhibition of NF-κB p50 transcription by Sox4, in addition to a reverse pattern of expression of Sox4 and NF-κB p50 in different stages of melanocytic lesions. Our results suggest that Sox4 regulates melanoma cell migration and invasion in an NF-κB p50-dependent manner and may serve as a prognostic marker and potential therapeutic target for human melanoma.