Objective To investigate the efficacy and safety of high-flow nasal cannula oxygen therapy (HFNC) in idiopathic pulmonary fibrosis (IPF) with respiratory failure. Methods A total of 90 patients with IPF and respiratory failure who were admitted in the hospital from May 2019 to April 2020 were selected, and they were divided into group A(nasal catheter oxygen uptake), group B [non-invasive positive pressure ventilation (NPPV)]and group C (HFNC) according to random number table method, with 30 cases in each group. The arterial blood gas (partial pressure of carbon dioxide [PaCO2], partial pressure of oxygen [PaO2], oxygen saturation [SpO2], power of hydrogen [pH]), 6-minute walking test (6MWT) distance, vital signs (heart rate and respiratory rate) and adverse reactions (incidence of nasal cavity dryness, nasal mucosal hemorrhage, flatulence, degree of xerostomia) were compared among the three groups. Results There were no statistically significant differences in the levels of PaCO2 and pH among the three groups before and after treatment (P＞0.05); the levels of PaO2 and SpO2 in the three groups after treatment for 1, 3 and 7 d were higher than those before treatment, the differences were statistically significant(P＜0.05); the levels of PaO2 and SpO2 in group B and group C were higher than those in group A after treatment for 1, 3 and 7 d, the differences were statistically significant(P＜0.05); there were no statistically significant differences in the levels of PaO2 and SpO2 between group B and group C after treatment for 1, 3 and 7 d (P＞0.05); the 6MWT distance of the three groups after treatment for 7 d was longer than that before treatment, the heart rate and respiratory rate were lower than those before treatment, the 6MWT distance of group B and group C was longer than those of group A, and the heart rate and respiratory rate of group B and group C were lower than those of group A, the differences were statistically significant (P＜0.05); there was no statistically significant difference in the 6MWT distance and vital signs between B group and C group after treatment for 7 d (P＞0.05); the incidence rates of nasal dryness, nasal mucosal bleeding, and flatulence in group C was lower than that of group A and group B, and the differences were statistically significant (P<0.05); the degree of dry mouth in the three groups was compared, group C was lighter than group A and group B, the difference was statistically significant(P<0.05). Conclusion HFNC in IPF with respiratory failure has significant effect, it can regulate arterial blood gas, stabilize vital signs, reduce adverse reactions, and relieve the degree of xerostomia of the patients.