Abstract Background Metformin is a standard treatment for type 2 diabetes mellitus (DM). Previous in vitro and in vivo studies have reported the association of metformin’s additive anticancer response with chemotherapy in esophageal cancer. However, no clinical studies have been reported. Therefore, this study is to aim the administration of metformin use can improve clinical outcomes of esophageal cancer patient with neoadjuvant combined chemotherapy and radiation (CCRT). Methods A total of 209 patients with esophageal cancer and underlying DM who underwent neoadjuvant CCRT before surgical resection were included from 1998 to 2022. There were 22 patients with metformin medication (10.5%) and 186 patients without metformin (89%). Univariable and multivariable regression analysis were done for complete response effect of metformin medication. Moreover, early clinical outcomes such as, overall survival and disease free survival were compared between the two groups. Results The complete response rate was higher for the metformin group (45.5% vs 22.6%; p = 0.019) and the recurrence rate was significantly lower (21.1% vs 45.7%, p = 0.040). The metformin group was associated with complete response rate in univariate logistic regression analysis (odds ratio [OR] = 2.86 [1.15–7.08], p = 0.023) and multivariable analysis (odds ratio [OR] = 2.84 [1.12–7.23], p = 0.028). Median follow-up duration was 19.8 months for metformin group, 17.3 months for non-metformin group. Overall 2-year survival rate and disease free survival was higher for metformin group than non-metformin group, (40% vs 26.5%, p = 0.380, 31.6% vs 24.3%, p = 0.095), however, not significant. Conclusion An association of metformin use with complete response rate in neoadjuvant CCRT esophageal cancer patients has been shown. The potential of metformin’s tumor response after neoadjuvant CCRT for esophageal cancer has been demonstrated in our study. Further prospective study should be needed for clinical evidence.