One of the aspects perplexing clinicians who take care of COVID-19 patients with pronounced arterial hypoxemia yet without proportional signs of respiratory distress, with even deceiving cyanosis, is that they don’t even express a sense of dyspnea. This phenomenon is referred as ‘happy or silent hypoxemia”. For clinicians the presence of happy or silent hypoxemia in Covid-19 patients, in spite of pronounced arterial hypoxemia, can erroneously lead to the conclusion that the patient is not in a critical condition. Those cases can quickly leapfrog clinical evolution stages and suffer ARDS, with concomitant cardio respiratory arrest and death. Pulse oximetry should be interpreted with caution, because left-sided shifting of the oxyhemoglobin dissociation curve. The pathophysiology of happy or silent hypoxemia might be explained by the following hypothesis. Hypoxia normally activates the carotid body chemoreceptors, and the afferent signals are relayed at the nucleus tractus solitarius through. This normally leads to an increase in respiratory rate and dyspnea sensation. SARS-CoV-2 infects the brain through the olfactory bulb and olfactory nerves, through trans-synaptic spread, finally reaching the brainstem, and the nucleus tractus solitarius. The inflammation of the nucleus of the tractus solitarius by the virus invasion incites that the afferent hypoxia stimuli from the carotid bodies may not be effectively relayed at the nucleus tractus solitarius, resulting in an impaired efferent respiratory response. This explains why COVID-19 patients show almost normal breathing in the presence of severe hypoxemia (Happy or silent hypoxia). Physicians should not only to trust on the patient’s seeming happiness but closely monitor respiratory rate, signs of hyperventilation, oxygen saturation and invasive measurements of hypoxemia/hypocapnia at regular time intervals.