Objective To explore the expression of OVO-like zinc finger 2 (OVOL2) protein in colorectal cancer tissues and its association with patient prognosis.Methods A total of 144 patients with colorectal cancer who underwent radical tumor resection at Tianjin People's Hospital from January 2019 to December 2020 were selected. All the surgical tissue samples of these patients were collected. The expressions of OVOL2 protein in 144 colorectal cancer tissues were detected by immunohistochemistry (IHC) staining, and the relationship between OVOL2 protein expression and clinicopathological characteristics was analyzed. After a 5-year follow-up, the Kaplan-Meier curve was used to analyze the overall survival rates of patients with negative and positive OVOL2 protein expression. Univariable and multivariable general Cox regression models were used to assess the prognostic value of OVOL2 in colorectal cancer.Results The positive expression rate of OVOL2 protein in colorectal cancer samples was 56.9% (82/144), while the negative expression rate was 43.1% (62/144). The positive rate of OVOL2 protein was higher in patients with TNM stage I-Ⅱ tumors and those without lymphovascular invasion (P < 0.05). The survival curve results showed that patients with positive expression of OVOL2 protein had a better prognosis than those with negative expression (P < 0.05). Among patients with TNM stage Ⅰ-Ⅱ tumors, those with positive expression of OVOL2 protein had a better prognosis than those with negative expression (P < 0.05). For patients with TNM stage Ⅲ tumors, those with positive expression of OVOL2 protein had a better prognosis than those with negative expression (P < 0.05). The results of univariable and multivariable Cox regression analysis demonstrated that TNM stage Ⅲ tumors [H^R = 1.935 (95% CI: 1.097, 3.414) ], lymphovascular invasion [H^R = 1.952 (95% CI: 1.067, 3.572) ], nerve invasion [H^R = 2.537 (95% CI: 1.417, 4.544) ] and negative expression of OVOL2 protein [H^R = 2.708 (95% CI: 1.522, 4.818) ] were all independent risk factors for death in patients with colorectal cancer (P < 0.05).Conclusion The OVOL2 protein shows negative expression in colorectal cancer tissues and is associated with tumor invasiveness and poor prognosis. OVOL2 is expected to become a potential molecular marker for prognosis assessment in colorectal cancer.