Objective To investigate the clinical effectiveness of high‑flow nasal cannula oxygen therapy (HFNC) with different inhalation flow on patients with postoperative hypoxemia. Methods A total of 40 patients with postoperative hypoxemia who were admitted to Department of Critical Care Medicine, the First Affiliated Hospital of Naval Medical University From December 2019 to June 2022, and underwent HFNC were selected. A self‑control study method was used. After receiving conventional nasal catheter oxygen therapy for 1 h, the patients underwent HFNC at inhalation flows of 30, 45, and 60 L/min for 1 h. Their heart rate, pulse oxygen saturation (SpO2), respiratory rate, systolic blood pressure (SBP), and mean arterial pressure (MAP) in four oxygen therapy stages were recorded. The blood gas analysis indexes [arterial partial pressure of oxygen (PaO2), arterial partial pressure of carbon dioxide (PaCO2), and pH], oxygenation index (OI), comfort, and tolerance were also recorded immediately after the end of the four stages. Results Compared with conventional nasal catheter oxygen therapy, HFNC at 30, 45, and 60 L/min resulted in increased PaO2 and OI (P<0.05), HFNC at 45 and 60 L/min resulted in a decreased respiratory rate (P<0.05) and increased SpO2 (P<0.05), and HFNC at 60 L/min resulted in reduced comfort and tolerance (P<0.05). Compared with HFNC at 30 L/min, PaO2 and OI increased after HFNC at 45 and 60 L/min (P<0.05), while the degree of comfort and tolerance decreased after 60 L/min HFNC (P<0.05). Compared with HFNC at 45 L/min, reduced comfort and tolerance were seen after 60 L/min HFNC (P<0.05). There was no significant difference in other indicators (P>0.05). Conclusions An increased inhalation flow of HFNC can improve the oxygenation of patients with postoperative hypoxemia, but excessive increases of inhalation flow does not necessarily bring additional benefits to patients. The inhalation flow of 45 L/min may balance the therapeutic effect, comfort and tolerance of HFNC.