Endometrial cancer (EC) is a prevalent gynecological malignancy that imposes significant health and economic burden on women worldwide. The aim of this study was to investigate the expression levels of G1 to S phase transition 2 (GSPT2) and cold-inducible RNA-binding protein (CIRBP) in endometrial cancer tissues relative to normal endometrial tissues and to evaluate their potential as biomarkers for diagnosis and prognosis. We conducted a prospective analysis involving RNA extraction, real-time polymerase chain reaction (RT-PCR), and immunohistochemistry (IHC) to assess gene expression and protein localization. Our findings revealed that GSPT2 was significantly overexpressed (t = 2.754, P = .008611), whereas CIRBP was underexpressed (t = 3.344, P = .001647) in EC tissues. Survival analysis demonstrated that high GSPT2 expression correlated with poor overall survival (OS) (P < .0001), in contrast to high CIRBP expression, which was associated with improved OS (P < .0001). Additionally, GSPT2 expression was positively correlated with aggressive pathological features, including higher tumor grading and International Federation of Gynecology and Obstetrics (FIGO) staging, Lymphovascular Space Invasion (LVSI) (P < .05), while CIRBP showed negative correlations with these characteristics (P < .05). These results underscored that high GSPT2 expression should be closely associated with EC progression and poor prognostic, while CIRBP exert a protective effect. The potential of GSPT2 as a poor prognostic marker and CIRBP as a favorable prognostic marker suggest their utility in guiding treatment decisions. Despite limitations such as a relatively small sample size and the lack of functional experiments, our study highlights GSPT2 and CIRBP as promising biomarkers for early diagnosis and targeted therapy in endometrial cancer. Future research should focus on larger cohorts and functional validations to further elucidate the roles of these biomarkers in clinical practice and personalized medicine approaches.