Objective To explore the predictive value of the systemic immune-inflammation index (SII) combined with myeloid ecotropic viral integration site 1 (MEIS1) levels for the prognosis of patients undergoing radical surgery for endometrial cancer.Methods This study included 92 endometrial cancer patients who underwent radical surgery at Handan First Hospital from October 2021 to September 2024. Patients who died after surgery were classified into the poor prognosis group (n = 20), while those who survived with good postoperative outcomes were classified into the good prognosis group (n = 72). Relevant data were collected from all patients before surgery and during follow-up, and the levels of carbohydrate antigen 125 (CA125), Ki-67, SII and MEIS1 mRNA were measured.Results The levels of CA125 and Ki-67 in the poor prognosis group were significantly higher than those in the good prognosis group (P < 0.05). The relative expressions of MEIS1 mRNA in both tumor and adjacent tissues of the poor prognosis group were significantly lower than those of the good prognosis group (P < 0.05). The SII before and after surgery was significantly higher in the poor prognosis group than in the good prognosis group (P < 0.05). Multivariable Logistic regression analysis showed that elevated preoperative CA125 levels [O^R = 1.873 (95% CI: 1.108, 3.166) ], elevated preoperative Ki-67 levels [O^R = 1.577 (95% CI: 1.049, 2.371) ], increased SII [O^R = 1.021 (95% CI: 1.006, 1.036) ], and decreased preoperative MEIS1 mRNA levels [O^R = 0.004 (95% CI: 0.000, 0.103) ] were all risk factors for poor prognosis in patients undergoing radical surgery for endometrial cancer (P < 0.05). Receiver operating characteristic curve analysis demonstrated that the sensitivities of MEIS1 mRNA levels, SII, and their combination for predicting postoperative prognosis in patients undergoing radical surgery for endometrial cancer were 85.0% (95% CI: 0.621, 0.968), 85.0% (95% CI: 0.621, 0.968), and 95.0% (95% CI: 0.751, 0.999), with the specificities being 94.4% (95% CI: 0.864, 0.985), 66.7% (95% CI: 0.546, 0.773), and 86.1% (95% CI: 0.759,0.931), respectively.Conclusion The combination of the SII and MEIS1 levels effectively predicts the prognosis of patients undergoing radical surgery for endometrial cancer, enhancing the accuracy of postoperative prognostic assessment.