Background: Novel coronavirus disease-2019 (COVID-19) has become a public emergency that is characterized by a dysregulated immune response and hypercoagulable state. The purpose of the present study was to evaluate NOTCH and tumor necrosis factor-alpha converting enzyme (TACE) levels in COVID-19-infected patients and assess their predictive value on the severity of the disease. Methods: A total of 116 severe-critical COVID-19 patients who were interned intensive care were included in the study. The severity of the disease was evaluated according to the WHO classification system. Patients were divided into two groups according to their cTroponin T (cTnT) levels. Patients who had cTnT levels at least five times the upper limit of normal constituted Group 1 (n = 58); patients who had normal cTnT levels constituted Group 2 (n = 58). Besides, 62 age- and sex-matched healthy controls, who applied to cardiology outward clinic were taken as a control group (Group 3). All patients underwent echocardiographic examination. NOTCH and TACE levels were assessed using enzyme-linked immunosorbent assay. Results: The average age of the patients was 59.96 ± 15.46 years, 92 (51.7%) were female and 86 (48.3%) were male. The mean length of hospital stay was 16.35 ± 10.97 days. NOTCH levels were significantly higher in Group 1 patients compared to Group 2 and control group of patients P = 0.001). NOTCH levels of Group 2 were significantly higher compared to the control group (P = 0.002). Similarly, the TACE levels of Group 1 were significantly higher than that of Group 2 and the control group (P = 0.001). Mortality and length of hospital stay were significantly higher in Group 1 patients compared to Group 2 patients (P = 0.002 and P = 0.004, respectively). TACE levels of deceased patients were significantly higher than that of live patients (P = 0.004). There was a positive relationship between the length of hospital stay and NOTCH levels in Group 1 patients (r = 0.527, P = 0.003). TACE and NOTCH levels were positively correlated with troponin levels (r = 0.627 and r = 0.671, respectively P < 0.001 for both). NOTCH value of 0.34 nmol/L and TACE value of 6.53 μg/mL predicted inhospital mortality with a sensitivity of 90.30% and 63.6% and specificity of 91.5% and 78.6%, respectively. Conclusion: Measurement of NOTCH and TACE levels during severe acute respiratory syndrome coronavirus infection could be helpful for risk stratification.