Objective To observe the dynamic changes in quality of life and its related influencing factors in elderly patients with esophageal cancer during radiotherapy. Methods A prospective trial was conducted on 123 elderly patients with esophageal cancer undergoing radiotherapy in our hospital from January 2022 to January 2023. In the early, middle and late stages of radiotherapy (at 1 d, 4 weeks after and the end of radiotherapy), quality of life questionnaire core-30 (QLQ-C30), hospital anxiety and depression (HAD) scale, simplified coping style questionnaire (SCSQ) and patient-generated subjective global assessment (PG-SGA) scale were used to survey the quality of life, having anxiety and depression, coping styles and baseline nutritional status in the patients. SPSS 22.0 software was used for data analysis. Multivariate linear regression model was applied to analyze the related factors affecting the quality of life of these patients during radiotherapy. Results Among the 123 elderly patients, 10 gave up due to various radiotherapeutic complications, and the remaining 113 cases completed the radiotherapy plan and related investigation. The scores of physical function, role function, emotional function, social function and total health score of QLQ-C30 scale showed downward trends in turn at the time points of before and in the early, middle and late stages of radiotherapy, and the differences between any two time points were statistically significant (all P<0.05). The scores of fatigue, pain, nausea and vomiting, as well as sleep disorders, loss of appetite, dyspnea and economic status were in upward trends in turn, and there were significant differences between the two time points (all P<0.05). Multivariate linear regression analysis indicated that family monthly income (β=0.311; P<0.001) and SCSQ (positive coping) (β=0.069; P=0.036) had a positive predictive effect, and clinical stage (β=-0.243; P<0.001) and HAD (anxiety) (β=-0.271; P<0.001) had a negative predictive effect on the QLQ-C30 scale score in the early stage of radiotherapy, and the above variables jointly explained 42.30% of the variation in the QLQ-C30 scale score in the early stage of radiotherapy. PG-SGA (≥9 points) (β=-0.766; P<0.001) and HAD (anxiety) (β=-0.183; P<0.001) had a negative predictive effect, and precision radiotherapy (β=0.322; P<0.001) and SCSQ (positive coping) (β=0.671; P<0.001) had a positive predictive effect on the QLQ-C30 scale score in the middle stage of radiotherapy, and these variables jointly explained 51.40% of the variation in the QLQ-C30 scale score in the middle stage of radiotherapy. PG-SGA (≥9 points) (β=-0.173; P=0.016), acute side effects of radiotherapy (β=-0.465; P=0.023), neurotoxicity (β=-0.365; P=0.024) and HAD (depression) (β=0.591; P<0.001) had a negative predictive effect, and precision radiotherapy (β=0.465; P=0.023) and SCSQ (positive coping) (β=0.311; P<0.001) had a positive predictive effect on the QLQ-C30 scale score in the late stage of radiotherapy, which together explained 48.60% of the variation in the QLQ-C30 scale score in the late stage of radiotherapy. Conclusion With the progress of radiotherapy, the quality of life of the elderly patients with esophageal cancer is gradually decreased. The factors affecting quality of life in different periods of radiotherapy is various. In clinical practice, taking targeted interventions based on the characteristics of patients in different periods of radiotherapy, and actively improving the negative coping style are of great significance in enhancing the quality of life of the patients during the whole period of radiotherapy.