Colon cancer is one of the most common malignancies causing the majority of cancer-related deaths worldwide. The tripartite motif family protein 72 (TRIM72), also known as mitsugumin 53, acts as an E3 ubiquitin ligase. TRIM72 is involved in insulin resistance and metabolic syndrome, which are risk factors of colon cancer. However, the correlation between TRIM72 and colon cancer remains unknown. In the present study, we explored the expression profile of TRIM72 in colon cancer tissues and the diagnostic value of serum TRIM72 in colon cancer. The receiver operating characteristic (ROC) curves were applied for evaluating the diagnostic value of serum TRIM72. We thus found that immunoreactive TRIM72 levels were significantly lower in colon cancer tissues than those in normal colon tissues. Moreover, serum TRIM72 levels were significantly lower in colon cancer patients than those in healthy volunteers. Importantly, the lower serum TRIM72 levels were associated with advanced clinical stage, lymph node, and distant metastases in colon cancer patients. The ROC curve analysis showed that serum TRIM72 has a superior diagnostic value (the area under the curve (AUC) = 0.829) than the traditional tumor biomarkers, carcinoembryonic antigen (CEA) (AUC = 0.707) and carbohydrate antigen 19-9 (CA199) (AUC = 0.750), and the combination of TRIM72 with CEA and CA199 showed the best diagnostic value for colon cancer (AUC = 0.928). In conclusion, serum TRIM72 may be a potential biomarker for the diagnosis and the prognosis of colon cancer.