Background: The coronavirus disease 2019 (COVID-19) pandemic impacted a huge number of people worldwide, with high morbidity and mortality. Consistent findings indicated a potential role of iron parameters, hyperferritinemia, and ferroptosis in the pathogenesis of multiorgan failure, and it might serve as a new treatment target. However, no single reliable marker of iron homeostasis exists, as all traditional parameters are influenced by inflammation. Studying soluble transferrin receptor (sTfR) and sTfR/log ferritin takes advantage of the reciprocal relationship between the two variables influenced by iron deficiency and may provide a better understanding of the iron derangement that occurs in COVID-19 infection. Aim: To assess the pattern of hepcidin, sTfR, and sTfR/log ferritin index in COVID-19 patients, its association with disease severity, complications, and mortality, as well as its validity to be used as a biomarker for complications, severity, and mortality. Patients and methods: It is a case–control study conducted at Suez Canal University Hospital. A 100 participants were selected and divided into two groups: a study group (50 adult COVID-19 patients) and a control group (50 healthy blood donor volunteers). Clinical data were obtained using a questionnaire, clinical examination, laboratorty, and radiological tests. All participants were tested for iron parameters: serum iron, total iron binding capacity, transferrin saturation percentage, ferritin, sTfR, and serum hepcidin. Results: COVID-19 patients showed a statistically significant higher sTfR, hepcidin, and sTfR/log ferritin index (P <0.0001) and statistically significant lower serum iron and total iron binding capacity (P <0.001). High sTfR was associated with higher mortality 58.1% and a lower percentage of recovery 41.9%. The relative risk of fatal outcome in the high sTfR subgroup is 4.07 times that in the normal sTfR subgroup. Conclusion: sTfR level and sTfR/log ferritin index are significantly elevated in COVID-19 infection. They could be considered significant biomarkers correlated to the severity, complications, and outcome of COVID-19 infection and add clinical value to predict disease progression among COVID-19 patients.