Background: D-dimer level exceeding 1 µg/ml is identified as a risk factor for mortality in adult COVID-19 patients. Objective: This study aimed to assess the role of D-dimer levels in predicting disease severity among COVID-19 infected patients in Egypt. Patients and Methods: A cross-sectional study included 100 patients with confirmed COVID-19 infection by reverse transcription polymerase chain reaction (RT-PCR) from oro-nasopharyngeal swabs, selected from the Isolation Departments of Menouf Fever Hospital and Sadat General Hospital. Fifty of them had severe COVID disease (Group I), and the other 50 (Group II) had mild to moderate COVID disease (i.e. hemodynamic stability without significant systemic illness). Results: Patients who died had a markedly higher mean D-dimer level compared to those still admitted (0.574 ± 0.305 mg/L) and those discharged (0.583 ± 0.466 mg/L), with significant differences between all groups except between those still admitted and those discharged (P=0.996). The ROC curve analysis for D-dimer levels showed strong diagnostic performance across different group comparisons. A cutoff of > 0.3 mg/L effectively distinguished cases from controls with an accuracy of 89.6%, sensitivity of 86.0%, and specificity of 80.0%. For distinguishing group I from group II, a cutoff of >1.3 mg/L yielded an accuracy of 88.6%, with 76.0% sensitivity and 92.0% specificity. A > 0.4 mg/L cutoff showed excellent accuracy (98.4%) in differentiating group I from group III, with 100% sensitivity and 84.0% specificity. Lastly, a > 0.3 mg/L cutoff achieved 80.7% accuracy in distinguishing group II from group III. Conclusion: Elevated D-dimer levels were linked to severe disease progression, higher mortality, and increased inflammation. ROC curve analysis confirmed D-dimer's diagnostic value, with accurate cutoffs for distinguishing between patient groups. These findings align with broader research, supporting D-dimer testing as a useful tool for predicting severe outcomes and improving COVID-19 management.