Platypnea-orthodeoxia syndrome (POS) is a rare disorder associated with coronavirus disease 2019 (COVID-19) pneumonia. However, POS may be underdiagnosed. We report the case of a 59-year-old female patient with POS complicated by pulmonary embolism in COVID-19. Imaging revealed ground-glass opacities predominantly in the lower lobes and a pulmonary embolus in the right upper lobe. She was diagnosed with POS due to marked postural discrepancies between supine and upright oxygen saturations and blood oxygenation. Intracardiac shunt, one of the etiologies of POS, was not detected by bubble contrast echocardiography, and postural de-saturation gradually improved with methylprednisolone and edoxaban administration. In our literature review, only 3 of the 16 patients with POS associated with COVID-19 had cardiac shunting, suggesting that moderate to severe COVID-19 causes POS without cardiac shunts. COVID-19-associated vasculopathy and lower lung lesion predominance in COVID-19 pneumonia may cause ventilation-perfusion mismatch due to gravitational shunting of blood into the poorly ventilated lower lungs in the upright position, which may ultimately cause POS. Hypoxemia impedes rehabilitation, whereas early initiation of supine positioning in bed, with knowledge of the pathophysiology of POS, may have a positive effect.