Background: Endometrial cancer (EC) staging is essential for effective treatment. Recent developments in molecular profiling have improved the management of EC through the identification of molecular subtypes that influence prognosis and the requirement for adjuvant therapies. This study aimed to evaluate clinical and diagnostic data together with immunohistochemical biomarker study related to molecular classification in patients with EC and to explore factors independently associated with the administration of adjuvant therapy. Methods: This retrospective study included 100 patients diagnosed with EC who underwent surgical intervention between October 2020 and October 2022. Data were obtained from clinical records and pathology reports. Patients were categorized based on whether they received adjuvant therapy. Multivariable logistic regression was used to identify independent factors associated with adjuvant therapy use. Results: Patients who received adjuvant therapy were older, had larger tumors, higher abnormal p53 staining (consistent with Tumor Protein 53 (TP53) mutation), and greater lymph node involvement. Independent predictors of adjuvant therapy included Stage IB (odds ratio (OR): 68.571, 95%confidence interval (CI): 10.540–446.114, p < 0.001), Stage II–IV (OR: 153.412, 95%CI: 15.048–1564.055, p < 0.001), and abnormal p53 stainings (OR: 8.572, 95% CI: 1.304–56.341, p = 0.025). Endometrioid carcinoma was negatively associated with adjuvant therapy (OR: 0.104, 95% CI: 0.012–0.911, p = 0.041). Conclusions: The results of this study indicate that abnormal p53 stainings, clinical staging, and the presence of endometrioid tumors are significant determinants for the administration of adjuvant therapy. Integration of clinical staging and exact diagnoses in addition to molecular profiling may improve treatment decisions.