Objective To observe the effect of elemene oral breast combined with docetaxel+oxaliplatin (DO) chemotherapy regimen on serum levels of miR-203 and miR-21 in patients with advanced esophageal cancer. Methods A total of 92 patients with advanced esophageal cancer who were treated in Nanyang Zhang Zhongjing Hospital from January 2017 to February 2019 were selected and divided into two groups according to the random number table method, with 46 cases in each group. The routine group was treated with DO, chemotherapy regimen and the study group was treated with elemene oral breast on the basis of the routine group. The objective response rate (ORR), disease control rate (DCR), immune function, serum tumor markers, serum levels of miR-203, miR-21 and changes of long-term survival were compared between the two groups. Results The ORR of the study group was 60.86%, which was higher than that of the routine group (39.13%, P<0.05); the DCR of the study group was 76.09%, which was higher than that of the routine group (56.52%, P<0.05). After treatment, the levels of NK and CD4 ⁺ in the study group were higher than those in the routine group, the level of CD8 ⁺ was lower than that in the routine group ( P<0.05). After treatment, the CEA, SCC, TSGF, NSE indexes in the study group were lower than those in the routine group ( P<0.05). After treatment,the level of miR-21 in the study group was higher than that in the routine group, and the level of miR-21 was lower than that in the routine group ( P<0.05). The two-year follow-up showed that the 1-year survival rate and the 2-year survival rate of the study group were higher than those of the routine group ( P<0.05). Conclusion Elemene oral breast combined with DO chemotherapy regimen in treatment of advanced esophageal cancer can effectively regulate the immune function of patients and the expression of miR-203 and miR-21, and prolong the survival period with significant effect.