Epithelial-mesenchymal transition (EMT) is a process during which normal epithelial cells acquire mesenchymal characteristics. EMT has a critical role in various human diseases especially in cancer. EMT facilitates tumor initiation and progression by mediating cancer cell stemness and motility. Zinc finger transcription factor SNAIL is one of the most important initiators of EMT. Therefore, it is of great significance to understand the regulating mechanism of SNAIL. In this study, we carried out a luciferase-based genome-wide screening using small interfering RNA library against ~200 of E3 ligases and ubiquitin-related genes and identified SOCS box protein SPSB3 as a novel E3 ligase component that targets SNAIL into polyubiquitination and degradation in response to GSK-3β phosphorylation of SNAIL. Functionally, we observed that SPSB3 overexpression greatly inhibits tumor metastasis by regulating SNAIL degradation both in vitro and in vivo. The expression of SPSB3 and SNAIL are negatively correlated in human esophageal squamous cell carcinoma tissues, and low SPSB3 expression indicates lymph node metastasis. Moreover, high SPSB3 expression indicates good survivals in various kinds of cancer. Collectively, these findings suggest that SPSB3-mediated SNAIL degradation has a vital role in regulating EMT and cancer progression.