This study was to evaluate the value of diffusion-weighted imaging (DWI) in predicting the efficacy of radiotherapy for esophageal cancer from xenograft model level. Thirty-two tumor-bearing mice from the Eca-109 cell line nude mice models were established. The experimental group (n = 16) received a single dose of 15 Gy (6MV X-ray), whereas the control group (n = 16) did not receive any treatment. The tumor volume and apparent diffusion coefficient (ADC) were obtained. The cell density, tissue necrosis ratio, and CD31 expression were determined at matched time points. The tumor volume was smaller in the experimental group than in the control group (P < 0.05) on the 7th day after radiotherapy (1.580 ± 0.965 cm3 vs. 2.671 ± 0.915 cm3). The ADC values were higher in the experimental group than in the control group on the 3rd day (P < 0.05) (998.15 ± 163.76 ×10- 6 mm2/s vs. 833.32 ± 142.15 ×10- 6 mm2/s). On the 3rd day after radiotherapy, the differences in cell density and necrosis ratio between the two groups were statistically significant; the tumor cell density was lower in the experimental group (25.56 ± 1.40%) than in the control group (33.48 ± 4.18%) (P < 0.05), and the proportion of tissue necrosis was higher in the experimental group (32.19 ± 1.21%) than in the control group (29.16 ± 2.16%) (P < 0.05). The negative and weak positive rate of CD31 expression in the experimental group was higher than the control group, whereas the generally positive and strong positive rate of CD31 expression was significantly lower than the control group in the early stage (P < 0.05). ADC values may change at the early stage before the morphological changes of tumors. Changes in cell density and necrosis ratio of transplanted tumors correspond to the changes in ADC values. DWI can be used for the early prediction of esophageal cancer radiotherapy efficacy.