Objective To explore the relationship between the morphological characteristics of colon cancer and the immunohistochemical expression of mismatch repair proteins and the clinicopathological stage, and to evaluate the diagnostic value of the combination of the two for advanced colon cancer. Methods: The clinical data of 100 patients with colon cancer who underwent radical surgical resection in our hospital from February 2022 to October 2025 were selected. The histopathological staging results of the patients were statistically analyzed, and the patients were divided into the early group (stage I-II, 52 cases) and the late group (stage III-IV, 48 cases) according to the pathological diagnosis results. The morphological characteristics and immunohistochemical expression results of mismatch repair proteins of the two groups were statistically analyzed and compared. Analyze the relationship between morphological features and staging, and evaluate the diagnostic efficacy of morphological features combined with mismatch repair status for the staging of colon cancer. Results: The proportions of poorly differentiated carcinoma, high-grade tumor budding, and vascular invasion in the advanced group were significantly higher than those in the early group (P < 0.05). The proportion of MSH6 protein deficiency in the advanced group was significantly higher than that in the early group (P < 0.05). Logistic regression analysis showed that the stage of colon cancer was related to low differentiation, high-grade tumor budding, vascular invasion, and MSH6 protein deficiency (P < 0.05), and the regression model was obtained: Lβ (Y) =-1.895+1.803× degree of differentiation +1.781× tumor budding grade +1.678× vascular invasion +1.735×MSH6 deletion. ROC curve analysis showed that the AUC of the regression model composed of poorly differentiated carcinoma, high-grade tumor budding, vascular invasion and MSH6 deletion in differentiating grade III-IV pathological changes was 0.851 (95%CI: 0.770-0.932), and the specificity, sensitivity and Youden index were respectively: 0.731, 0.958, and 0.689 have relatively high diagnostic value. Conclusion: Poorly differentiated, high-grade tumor budding, vascular invasion and MSH6 protein deficiency are closely related to the pathological stage of advanced colon cancer. Combined detection can assist routine pathological examination and provide a reference for stage determination.