Objective: To explore the application value of immunohistochemistry (IHC) combined with Sanger sequencing versus next-generation sequencing (NGS) in the molecular classification of endometrial carcinoma (EC). Methods: Clinical data of 123 patients with EC between October 2019 and June 2023 were retrospectively analyzed. Among them, 48 cases were classified using IHC combined with Sanger sequencing, and 75 cases were classified using NGS technology. The molecular classification results of the two groups were compared. Additionally, 10 representative samples covering the four molecular subtypes, POLE ultramutated(POLEmut), mismatch repair deficiency(dMMR), no specific molecular profile(NSMP), and p53 abnormal(p53abn), with varying clinical stages and histological grades were selected for a comparative analysis of the results obtained from IHC combined with Sanger sequencing and NGS. Results: Among the 123 EC patients, 12(9.7%) were POLEmut, 31(25.2% ) were dMMR, 67(54.5% ) were NSMP, and 13 (10.6%) were p53abn. Of the 48 cases assessed by IHC combined with Sanger sequencing, 1(2.1% ) was POLEmut, 12(25.0%) were dMMR, 29(60.4%) were NSMP, and 6(12.5%) were p53abn. Among the 75 cases assessed by NGS, 11(14.7%) were POLEmut, 19 (25.3%) were dMMR, 38(50.7%) were NSMP, and 7(9.3%) were p53abn. The validation experiment on 10 samples showed that IHC combined with Sanger sequencing and NGS yielded completely consistent results in detecting POLE mutations and microsatellite status. However, IHC had a 10% (1/10) missed detection rate for aberrant p53 expression. Conclusion: IHC combined with Sanger sequencing and NGS show good consistency in the molecular classification of EC. Nevertheless, NGS offers advantages in detecting POLE mutations and complex subtypes, contributing to improved classification accuracy and reduced risk of clinical misjudgment.