Objective: To analyze the mechanism of metformin in improving oxaliplatin resistance of colorectal cancer cells. Methods: The expression levels of EIF3G in 71 cases of colorectal cancer and adjacent tissues were detected by RT-qPCR. The survival curve was established by Kaplan-Meier method. The survival rate difference between the two groups was compared by Log-rank test.HCT-116 cells were infected with shEIF3G lentivirus, HCT-116 L-OHP-resistant cell line was constructed.After treated with metformin, sensitivity to L-OHP was detected by CCK-8 assay, RT-qPCR and Western blot were used to analyze the EIF3G mRNA and protein levels. The subcutaneous tumor model of nude mice was constructed to observe the effect of metformin on tumor growth. Results: The expression level of EIF3G mRNA in colorectal cancer tissues was up-regulated by (3.24±0.43) times compared with paraneoplastic tissues (P<0.01). EIF3G level was significantly correlated with the prognosis of colon cancer patients. Knockdown EIF3G could enhance the L-OHP sensitivity of HCT116/L-OHP cells (P<0.05); Metformin can reduce the expression level of EIF3G and improve the drug resistance of HCT116/L-OHP cells (P<0.05), and inhibit the development of colorectal cancer in vivo (P<0.05). Conclusion Metformin can inhibit the expression of EIF3G and improve the L-OHP resistance of HCT-116 cells.