Abstract: Objective To evaluate the efficacy of paclitaxel plus carboplatin chemotherapy in combination with radiotherapy for patients with high-risk endometrial cancer (EC). Methods A retrospective analysis was conducted on 120 patients with high-risk EC admitted to the Yellow River Sanmenxia Hospital from April 2022 to April 2023. According to the treatment regimen, they were divided into two groups, the control group (n = 60) received paclitaxel plus carboplatin chemotherapy, and the observation group (n = 60) received paclitaxel plus carboplatin chemotherapy combined with radiotherapy. The chemotherapy response, serum tumor marker levels, tumor suppressor gene levels, adverse reactions, and prognosis were compared between the two groups. Results After 4 cycles of chemotherapy, both the tumor response rate and disease control rate in the observation group were higher than those in the control group (P ＜ 0.05). There was no statistically significant difference in the overall incidence of adverse reactions between the two groups (P ＞ 0.05). After 4 cycles of chemotherapy, the serum levels of carcinoembryonic antigen (CEA), carbohydrate antigen (CA153), and cancer antigen 125 (CA125) in the observation group were significantly lower than those in the control group (P ＜ 0.05); conversely, the expression levels of p53 and p16 genes were higher than those in the control group (P ＜ 0.05). After 2 years of follow-up, the 2-year tumor recurrence rate and lymph node metastasis rate in the observation group were significantly lower than those in the control group (P ＜ 0.05); and the 2-year progression-free survival rate and overall survival rate were significantly higher than those in the control group (P ＜ 0.05). Conclusion The combination of paclitaxel plus carboplatin chemotherapy and radiotherapy demonstrates an effective improvement in prognosis for high-risk EC patients while maintaining good efficacy and reliable safety profiles.