Tripartite motif-containing 22 (TRIM22), a member of the tripartite motif protein family, has emerged as a putative tumor suppressor in various cancers. Nevertheless, its specific role and clinical significance in colorectal cancer (CRC) remain poorly characterized. Herein, we observed that TRIM22 expression was frequently downregulated in primary CRC tissues and was significantly correlated with better prognosis. Functional assays demonstrated that TRIM22 overexpression substantially attenuated the metastatic potential of CRC cells both in vitro and in vivo. Mechanistically, our results revealed that TRIM22 directly interacts with and ubiquitinates β-Catenin, a crucial transcription factor that drives CRC metastasis by modulating the epithelial-mesenchymal transition (EMT) process. Additionally, our data indicated that the anti-metastatic effect of TRIM22 relies on the degradation of β-catenin. In summary, this study is the first to deliberate the vital anti-tumor role of TRIM22 in CRC metastasis. We also provide new evidence suggesting that TRIM22 could be a prognostic marker and therapeutic target for inhibiting CRC progression.