High-flow nasal cannula (HFNC) oxygen therapy, which is important in noninvasive respiratory support, is increasingly being used in critically ill neonates with respiratory failure because it is comfortable, easy to set up, and has a low incidence of nasal trauma. The advantages, indications, and risks of HFNC have been the focus of research in recent years, resulting in the development of the application. Based on current evidence, we developed guidelines for HFNC in neonates using the grading of recommendations assessment, development and evaluation (GRADE). The guideline was formulated after extensive consultations with neonatologists, respiratory therapists, nurse specialists, and evidence-based medicine experts. We have proposed 24 recommendations for 9 key questions. This guideline aims to be a source of evidence and references of HFNC oxygen therapy in clinical practice, and so that more neonates and their families will benefit from HFNC.