Objective: To screen genes related to oxaliplatin resistance in colon cancer and verify the influence of them on the oxaliplatin treatment of colon cancer. Methods: Data set GSE42387 was downloaded and analyzed comprehensively, and oxaliplatin resistance genes were screened. Ualcan and GEPIA databases were used to detect the expression of drug-resistant genes in colon cancer and their influence on prognosis. Transfection of siRNA-ZIP8 interfered with ZIP8 expression in colon cancer cells SW620. CCK-8 proliferation assay detected the effect of oxaliplatin on colon cancer cell proliferation after ZIP8 expression was inhibited. Flow cytometry was used to detect the effect of oxaliplatin on colon cancer cell apoptosis after the expression of ZIP8 was decreased. Immunohistochemical staining was performed on colon cancer tissue samples before chemotherapy to evaluate the relationship between ZIP8 and chemotherapy effect. Results: Four drug-resistant genes (ZIP8, NUPR1, SLC43A1 and TEME73) were selected. ZIP8 was highly expressed in colon cancer tissues (P < 0.05) and correlated with patient prognosis (P=0.005). Under the same drug concentration, the proliferation rate of the siZIP8 group was significantly lower than that in the siNC group, the half inhibitory concentration of oxaliplatin in the siZIP8 group was lower than that in the siNC group (P < 0.05). Patients with low ZIP8 expression had longer overall survival (P = 0.001) and disease-free survival (P < 0.001). Conclusion: ZIP8 promotes oxaliplatin resistance in colon cancer patients and can be used as an indicator for the prognosis of chemotherapy.