The E3 ligase UBR5 is aberrantly expressed in diverse types of cancer. However, its expression pattern and biological function in colorectal cancer (CRC) remain unclear. We used RT-PCR, Western blot, and immunohistochemistry to measure UBR5 expression in CRC tissues and corresponding non-tumor tissues. The expression pattern of UBR5 in CRC tissues was determined by scoring system of immunohistochemical analysis and mRNA level by RT-PCR. The statistical analyses were applied to evaluate the associations of UBR5 expression with survival rate of patients. The UBR5 gene was overexpressed or silenced with lentiviral vectors in CRC cells. And, cell proliferation and apoptosis were measured using CCK8 assay and flow cytometry. We found that UBR5 is abundantly overexpressed in CRC tissues than adjacent non-cancerous tissues. We also found that high UBR5 level is positively correlated with progression and poor survival in CRC patients. In addition, further multivariate analysis indicated that UBR5 and TNM stage were independent prognostic factors for overall survival in patients with CRC. Furthermore, we demonstrated that the expression of UBR5 was significantly elevated in CRC cell lines. Overexpression of UBR5 enhanced in vitro cell proliferation and promoted in vivo tumor growth, whereas silencing UBR5 suppressed growth of CRC cells. Moreover, our findings show that UBR5 promotes CRC cell proliferation by inducing cell cycle progression and suppressing cell apoptosis. Finally, we found that UBR5 directly binds to the tumor suppressor esophageal cancer-related gene 4 (ECRG4) and increased its ubiquitination to reduce the protein stability of ECRG4. We identified a tumorigenic role of UBR5 in CRC and provided a novel therapeutic target for CRC patients.