Background: Thyroid hormones (TH) are essential for cellular growth, differentiation, and energetic regulation. Critical illness is frequently associated with alterations in TH metabolism not caused by abnormalities of the hypothalamic-pituitary-thyroid function. These changes, collectively known as non-thyroidal illness syndrome (NTIS). This study aimed to investigate the role of NTIS in prediction of mortality in ICU Patients. Methods: This prospective cohort study was carried out on 50 ICU patients in the Department of Intensive Care Unit in Benha University Hospitals. After diagnosis of NTIS patients were categorized into two groups: Non-NTIS group and NTIS group. Results: Multivariate regression analysis identified ALT, SAPS III, APACHE II, sepsis, ARDS, mechanical ventilation, liver cell failure, and ICU length of stay as significant independent predictors of NTIS. For in-hospital mortality, WBC count, albumin, ALT, NTIS, APACHE II score, ARDS, need for mechanical ventilation, liver cell failure, and ICU length of stay were identified as significant predictors. Our ROC curve analysis demonstrated that both fT3 and fT4 levels have good diagnostic performance in predicting in-hospital mortality. A cut-off value of fT3 < 2 pmol/L showed 90.8% sensitivity and 81.3% specificity, while fT4 < 10 pmol/L demonstrated 90.9% sensitivity and 85.2% specificity. Conclusions: our study demonstrates that NTIS is common among ICU patients and is associated with increased disease severity, higher complication rates, and increased mortality. The strong predictive value of fT3 and fT4 levels for in-hospital mortality suggests that thyroid function tests could be valuable additions to prognostic models in the ICU setting.