BACKGROUND: Colorectal cancer (CRC) is a common malignant tumor of the digestive tract worldwide, characterized by high incidence and mortality rates. AIM: To investigate the expression of serum apurinic/apyrimidinic endonuclease 1 autoantibodies (APE1-AAbs), peripheral pentraxin-3 (PTX-3), and miR-486-3p in patients with CRC undergoing radical surgery and their relationship with postoperative recurrence and metastasis. METHODS: A retrospective analysis was conducted on the clinical data of 154 CRC patients who underwent laparoscopic radical surgery in our hospital from January 2022 to January 2024. Patients were followed for one year postoperatively and divided into an occurrence group ( = 28) and a non-occurrence group ( = 126) based on whether they experienced recurrence or metastasis. The clinical data and the expression levels of APE1-AAbs, PTX-3, and miR-486-3p were compared between the two groups. Multivariate logistic regression analysis was performed to identify risk factors for postoperative recurrence and metastasis in CRC patients. The relationship of APE1-AAbs, PTX-3, and miR-486-3p with postoperative recurrence and metastasis was analyzed using Spearman correlation analysis. Receiver operating characteristic curves were drawn to evaluate the predictive value of serum APE1-AAbs, PTX-3, and miR-486-3p levels alone and their combination for postoperative recurrence and metastasis in CRC. RESULTS: The occurrence group had significantly higher proportions of patients with an age ≥ 60 years, lymph node metastasis, stage III disease, poor differentiation, tumor diameter > 5 cm, and higher platelet count, carcinoembryonic antigen, and carbohydrate antigen 19-9 levels than the non-occurrence group ( < 0.05). The expression levels of APE1-AAbs, PTX-3, and miR-486-3p in the occurrence group were significantly higher than those in the non-occurrence group ( < 0.05). Multivariate logistic regression analysis showed that lymph node metastasis, stage III disease, poor differentiation, and elevated levels of APE1-AAbs, PTX-3, and miR-486-3p were risk factors for postoperative recurrence and metastasis in CRC patients (odds ratio > 1, < 0.05). Spearman correlation analysis revealed that the levels of APE1-AAbs, PTX-3, and miR-486-3p were positively correlated with postoperative recurrence and metastasis in CRC patients ( = 0.642, 0.653, and 0.631, respectively, < 0.05). Receiver operating characteristic curve analysis showed that the area under the curve values for APE1-AAbs, PTX-3, and miR-486-3p levels alone and their combination in predicting postoperative recurrence and metastasis in CRC were 0.764, 0.783, 0.806, and 0.875, respectively, with the combination significantly outperforming individual markers ( < 0.05). CONCLUSION: Serum APE1-AAbs, PTX-3, and miR-486-3p levels are higher in CRC patients with postoperative recurrence and metastasis. These three markers are risk factors for postoperative recurrence and metastasis in CRC and can be used as predictive biomarkers. The combined detection of these markers has higher predictive value compared to individual tests.