The delayed prediction of high-flow nasal cannula (HFNC) failure is associated with poor prognosis in patients with acute respiratory failure (ARF) treated with HFNCs. This study aimed to identify the early predictors for requiring mechanical ventilation (MV) in ARF patients treated with HFNCs. This was a single-center retrospective observational study based on ARF patients older than 18 years, treated with HFNC, and had chest computed tomography (CT) scans performed in the emergency department (ED) of a tertiary hospital between July 2018 and June 2020. The demographic and laboratory data were collected, and the cross-sectional area (CSA) of the diaphragmatic crus was measured on the chest CT scan. Two hundred and twenty-nine patients with ARF (92 females and 137 males) were treated with HFNCs during the study period and included in this study. Twenty-five female patients (27.17%) and 32 male patients (23.36%) required subsequent intubation and MV and were categorized as HFNC failures. Their respiratory rate-oxygenation (ROX) indexes were acquired at two hours, and the average CSA of the diaphragmatic crura was integrated to analyze the predictive power, which showed good predictive accuracy in both gender groups (area under the receiver operating characteristic curves (AUROC) for females, 0.778, and males, 0.782). The optimal ROC curve cutoff point for the average CSA of the diaphragmatic crus was estimated to be 1.48 cm2 in female patients and 1.64 cm2 in male patients. Altogether, these results indicated that the CSA measurement of the diaphragmatic crus on CT in ARF patients might help predict the risk of HFNC failure.