Uterine corpus endometrial cancer (UCEC) is the sixth most common female cancer worldwide, with an increasing incidence. Improving the prognosis of patients living with UCEC is a top priority. Endoplasmic reticulum (ER) stress has been reported to be involved in tumor malignant behaviors and therapy resistance, but its prognostic value in UCEC has been rarely investigated. The present study aimed to construct an ER stress-related gene signature for risk stratification and prognosis prediction in UCEC. The clinical and RNA sequencing data of 523 UCEC patients were extracted from TCGA database and were randomly assigned into a test group (n = 260) and training group (n = 263). An ER stress-related gene signature was established by LASSO and multivariate Cox regression in the training group and validated by Kaplan-Meier survival analysis, Receiver Operating Characteristic (ROC) curves and nomograms in the test group. Tumor immune microenvironment was analyzed by CIBERSORT algorithm and single-sample gene set enrichment analysis. R packages and the Connectivity Map database were used to screen the sensitive drugs. Four ERGs (ATP2C2, CIRBP, CRELD2 and DRD2) were selected to build the risk model. The high-risk group had significantly reduced overall survival (OS) (P < 0.05). The risk model had better prognostic accuracy than clinical factors. Tumor-infiltrating immune cells analysis depicted that CD8+ T cells and regulatory T cells were more abundant in the low-risk group, which may be related to better OS, while activated dendritic cells were active in the high-risk group and associated with unfavorable OS. Several kinds of drugs sensitive to the high-risk group were screened out. The present study constructed an ER stress-related gene signature, which has the potential to predict the prognosis of UCEC patients and have implications for UCEC treatment.