The aim of the present study was to evaluate the therapeutic effect of high-flow nasal cannula (HFNC) oxygen therapy on patients with aspiration pneumonia accompanied by respiratory failure in the post-stroke sequelae stage, with the goal of providing more effective oxygen therapy and improving patient prognosis. Retrospective analysis was conducted on 103 elderly patients with post-stroke aspiration pneumonia and moderate respiratory failure (oxygenation index: 100-200 mmHg) that had been admitted. The patients were divided into two groups according to the mode of oxygen therapy that was used: the Venturi mask group and the HFNC treatment group. The two groups were analyzed and compared in terms of the changes in the blood gas indices measured at different points in time (4, 8, 12, 24, 48, and 72 h), the proportion of patients that required transition to invasive auxiliary ventilation, and the 28-day mortality rate. A total of 103 patients were retrospectively analyzed; 16 cases were excluded, and 87 patients were included in the final patient group (42 in the HFNC group and 45 in the Venturi group). There was a statistically significant difference in the oxygenation indices of the HFNC group and the Venturi group (F = 546.811, P < 0.05). There was a statistically significant interaction between the monitored oxygenation indices and the mode of oxygen therapy (F = 70.961, P < 0.05), and there was a statistically significant difference in the oxygenation indices for the two modes of oxygen therapy (F = 256.977, P < 0.05). HFNC therapy contributed to the improvement of the oxygenation indices at a rate of 75.1%. The Venturi and HFNC groups also differed significantly in terms of the proportion of patients that required transition to invasive auxiliary ventilation within 72 h (P < 0.05). The HFNC group's risk for invasive ventilation was 0.406 times that of the Venturi group (P < 0.05). There was no statistical difference in the 28-day mortality rate of the two groups (P > 0.05). HFNC could significantly improve the oxygenation state of patients with post-stroke aspiration pneumonia and respiratory failure, and it may reduce the incidence of invasive ventilation.