Colorectal cancer (CRC) is one of the most common malignant tumors worldwide, which is a heterogeneous disease and main risk factors are associated with inflammation, family history, genetic mutations, epigenetics, and so on. Ring finger domain proteins have been reported involved in carcinogenesis, whereas their roles in CRC are rarely studied. Here, we reanalyzed the expression of 202 RNF family members in CRC using published microarray data from GEO database and found that RNF183 is markedly upregulated in tumor tissues. RNF183 high expression is significantly associated with tumor size (P= 0.012), tumor invasive depth (P= 0.004), TNM stage (P= 0.01), and distant metastasis (P= 0.009). CRC patients with high expression of RNF183 have poor overall survival (P< 0.001) and progression-free survival (P< 0.001). Functional studies suggest that RNF183 facilitates growth, migration, and invasion of CRC cells in vitro and promotes tumor proliferation and metastasis in vivo. Mechanistically, RNF183 activates NF-κB signal pathway through P65 and stimulates the transcription of multifunctional chemokine IL-8. Blockage of NF-κB by small molecule inhibitor or depletion of IL-8 by siRNA attenuates the function of RNF183 to promote cell migration. Moreover, the regulation of RNF183 on IL-8 transcription and cell viability/motility is dependent on its E3 ubiquitin ligase activity. Our study provided proof of principle to show that RNF183 promotes proliferation and metastasis of CRC cells via activation of NF-κB-IL-8 axis.