Background: The prediction of high-flow nasal oxygen (HFNO) failure in patients with coronavirus disease-2019 (COVID-19) having acute respiratory failure (ARF) may prevent delayed intubation and decrease mortality. Aims: To define the related risk factors to HFNO failure and hospital mortality Study Design: Retrospective cohort study. Methods: To this study, 85 critically ill patients (≥18 years) with COVID-19 related acute kidney injury who were treated with HFNO were enrolled. Treatment success was defined as the de-escalation of the oxygenation support to the conventional oxygen therapies. HFNO therapy failure was determined as the need for invasive mechanical ventilation or death. The patients were divided into HFNO-failure (HFNO-F) and HFNO-success (HFNO-S) groups. Electronic medical records and laboratory data were screened for all patients. Respiratory rate oxygenation (ROX) index on the first hour and chest computed tomography (CT) severity score were calculated. Factors related to HFNO therapy failure and mortality were defined. Results: This study assessed 85 patients (median age 67 years, 69.4% male) who were divided into two groups as HFNO success (n = 33) and HFNO failure (n = 52). The respiratory rate oxygenation (ROX) was measured at 1 hour and the computed tomography (CT) score indicated HFNO failure and intubation, with an area under the receiver operating characteristic of 0.695 for the ROX index and 0.628 for the CT score. A ROX index of <3.81 and a CT score of >15 in the first hour of therapy were the predictors of HFNO failure and intubation. Age, Acute Physiology and Chronic Health Evaluation II score, arterial blood gas findings “(i.e., partial pressure of oxygen [PaO2 ], PaO2 [fraction of inspired oxygen]/SO2 [oxygen saturation] ratio)”, and D-dimer levels were also associated with HFNO failure; however, based on logistic regression analysis, a calculated ROX on the first hour of therapy of <3.81 (odds ratio [OR] = 4.78, 95% confidence interval [CI] = 1.75–13.02, P = 0.001) and a chest CT score of >15 (OR = 2.83, 95% CI = 1.01–7.88, P = <0.001) were the only independent risk factors. In logistic regression analysis, a ROX calculated on the first hour of therapy of <3.81 (OR = 4.78, [95% CI = 1.75–13.02], P = 0.001) and a chest CT score of >15 (OR 2.83, 95% CI = 1.01–7.88, P = <0.001) were the independent risk factors for the HFNO failure.