Background: FOLFOX4 chemotherapy is one of the most widely used adjuvant therapies in patients with stage III colon cancer after surgical resection. However, chemotherapy resistance is associated with a poor prognosis. The prognostic impact of high blood sugar levels on oxaliplatin resistance in CRC patients is an unexplored topic. Methods: A total of 157 patients with stage III CRC were classified according to their serum blood sugar level (≥ 126 or < 126 mg/dL). Clinicopathological features and clinical outcomes (oxaliplatin resistance) of the two groups were analyzed. Results: Through multivariate analysis, both disease-free and overall survival of CRC patients was found to be significantly associated with serum blood glucose levels (both P< 0.05) but not DM history. In vitro cell proliferation assay was performed through D-(+)-glucose administration. After metformin administration, enhanced proliferation of CRC cells with D-(+)-glucose administration could be reversed and oxaliplatin sensitivity considerably increased (P< 0.05). Furthermore, phosphorylation of two glycolysis-related target proteins, SMAD3 and MYC, notably increased with high glucose concentration. Conclusions: In summary, hyperglycemia could affect clinical outcomes in CRC patients receiving adjuvant chemotherapy, with the underlying oxaliplatin resistance mechanism possibly associated with increasing phosphorylation of SMAD3 and MYC and upregulation of G9A expression.