Background Hypoxemia sometimes occurs in the emergency room in the patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI), even in those with administration of conventional high-flow oxygen inhalation. The objective of the present study was to evaluate the effectiveness of non-invasive ventilation (NIV) in improving blood oxygen content and hemorheology in patients with AMI and hypoxemia. Methods This prospective study enrolled 50 consecutive eligible patients with AMI (aged 72.3 +/- 9.5 years), who had undergone PCI and been administered high-flow oxygen but still had hypoxemia. Blood was taken before NIV and at 0.5, 1, and 2 h after NIV. Blood gases, hemorheological variables including erythrocyte deformability, erythrocyte aggregation, erythrocyte osmotic fragility, membrane fluidity, and oxidative stress level were measured. Results Blood PaO2 increased to normal by 1 h after NIV. Assessed hemorheological variables had all improved and plasma malondialdehyde concentration decreased significantly after 2 h of NIV. Conclusions Our data suggest that NIV can help to improve blood oxygen content, hemorheological status, and minimize plasma lipid peroxidation injury in hypoxemic patients with AMI who have undergone PCI.