A cohort of chronic obstructive pulmonary disease patients experience acute exacerbations (AECOPD) presenting with worsening sputum production, cough and breathlessness. The recommended treatment for AECOPD involves using a 28% Venturi mask to achieve an arterial oxygen saturation of 88–92%. These guidelines have been poorly adhered to with many health professionals still administering high flow oxygen. An AECOPD model, created on the human patient simulator, was administered with 28% or 100% oxygen. 28% oxygen relieved hypoxia (PaO2 = 84.9 mmHg), caused mild hypercapnia (PaCO2 = 49.6 mmHg) and the blood pH was normal (pH = 7.37). 100% oxygen enabled better arterial oxygenation (PaO2 = 129.3 mmHg) but caused severe hypercapnia (PaCO2 = 100.9 mmHg) and acidosis (pH = 6.98). Preclinical medical students were randomly allocated to simulation or lecture-based learning (the study has a crossover design) and were taught the correct use of oxygen administration. A greater proportion of students rated they had an excellent understanding of the key learning points after simulation (100%) compared to the lecture- based learning (33%) and it was sufficient to significantly improve test scores (p = 0.0135). Simulation could be used to educate future health professionals in using 28% oxygen to reduce the risk of hypercapnic respiratory acidosis in AECOPD.