Objective To investigate the clinical efficacy and safety of a sequential treatment strategy involving high-flow nasal cannula oxygen therapy (HFNC) and non-invasive positive pressure ventilation (NPPV) in patients with advanced lung cancer complicated by respiratory failure. Methods The clinical data of 82 patients with advanced lung cancer complicated by respiratory failure who were admitted to the 989th Hospital of the Joint Support Force of the People’s Liberation Army of China from January 2023 to December 2025 were retrospectively included. According to the different treatment plans, the patients were divided into the control group (n＝41, treated with conventional NPPV) and the observation group (n＝41, treated with sequential HFNC and NPPV). Comparisons were made between the two groups regarding blood gas analysis indicators [arterial partial pressure of oxygen (PaO2), arterial partial pressure of carbon dioxide (PaCO2), oxygenation index], vital signs [heart rate and respiratory rate (RR)], pulmonary function indicators [forced expiratory volume in the first second percent-predicted (FEV1%), forced vital capacity (FVC)], inflammatory factor levels [C-reactive protein (CRP), interleukin-6 (IL-6)], and clinical outcomes indicators [total mechanical ventilation time, intensive care unit (ICU) hospitalization time, 28-day mortality, incidence of ventilator-associated pneumonia (VAP), treatment failure rate]. Results After 24 hours of treatment, the PaO2, PaCO2, oxygenation index, heart rate, and RR in both groups improved compared with those before treatment (all P＜0.05), and the improvement in the observation group was superior to that in the control group (all P＜0.05). On the 7th day of treatment, both groups showed improvement in FEV1% and FVC compared to before treatment (all P＜0.05), and the improvement degree in the observation group was significantly better than that in the control group (all P＜0.05); on the 3rd day of treatment, both groups showed a decrease in CRP and IL-6 compared to before treatment (all P＜0.05), and the decrease in IL-6 in the observation group was greater (P＜0.05), while there was no statistically significant difference in CRP between the two groups (P＝ 0.063). Compared with the control group, the total mechanical ventilation time and ICU hospitalization time in the observation group were shorter (all P＜0.05), and the incidence of VAP was lower (P＜0.05). There were no statistically significant difference in the treatment failure rate and 28-day mortality between the two groups (all P＞0.05). Conclusion For patients with advanced lung cancer complicated by respiratory failure, compared with single NPPV treatment, the sequential treatment strategy of HFNC and NPPV can more effectively improve oxygenation and ventilation functions, shorten the duration of respiratory support, and reduce the risk of VAP.