Objective To investigate the quality of life (QOL) in elderly patients with endometrial cancer after chemotherapy and analyze its influencing factors. Methods A questionnaire survey was conducted on 158 elderly patients with postoperative chemotherapy for endometrial cancer from June 2018 to June 2023. Their QOL level was assessed by endometrial cancer module of the fourth edition of functional assessment of cancer therapy-general (FACT-G). According to their score of FACT-G, they were divided into good QOL group (≥ average level, 82 cases) and poor QOL group (< average level, 76 cases). Pathological stage and type, differentiation grade, chemotherapy regimen and other data were collected. SPSS statistics 24.0 was used for data analysis. Depending on data type, Chi-square test or student′s t test was applied for intergroup comparison, and logistic regression analysis was adopted to identify the influencing factors for poor QOL in elderly patients with postoperative chemotherapy for endometrial cancer. Results The average score of FACT-G was (79.68±10.85) points in the 158 patients. The poor QOL group had significantly higher mutation rate of p53 in tumor foci, incidence of adverse reaction grades 3-4 and rates of depression, anxiety and fear of cancer recurrence than the good QOL group (P<0.05). Logistic regression analysis showed that p53 mutation (OR=2.670,95%CI 1.343-5.309), adverse reaction grades 3-4 (OR=4.646,95%CI 2.734-7.896), depression (OR=2.612,95%CI 1.315-5.186), anxiety (OR=3.284,95%CI 1.787-6.036) and fear of cancer recurrence (OR=3.442,95%CI 1.892-6.262) were risk factors for poor QOL in elderly patients with postoperative chemotherapy for endometrial cancer. Conclusion Molecular type in tumor foci, severe adverse reactions and negative emotions such as depression, anxiety and fear of cancer recurrence are important reasons for the decline of QOL in elderly patients with endometrial cancer after chemotherapy. It is necessary to formulate targeted physiological and psychological intervention measures so as to enhance their QOL in clinical practice.