This study aimed to investigate the effects of sustained hypoxic exposure on cerebral and muscle oxygenation and cardiorespiratory function at rest. Eleven healthy subjects inhaled a normobaric hypoxic (FiO2=0.12) or normoxic (FiO2=0.21) gas mixture for 4 h at rest, on two separated blinded sessions. Arterial oxygen saturation (SpO2), heart rate variability (HRV), end-tidal CO2 (EtCO2), and oxygenation of quadriceps muscle, prefrontal and motor cortices assessed by near-infrared spectroscopy (NIRS) were measured continuously during each session. Acute mountain sickness symptoms were evaluated at the end of each session. During a hypoxic session, SpO2 reduction (∼13%) plateaued after 20 min, while deoxygenation pattern took 30 to 40 min at the cerebral sites to plateau (+5.3±1.6 μMol of deoxygenated-hemoglobin). Deoxygenation was more pronounced in the cerebral cortex compared to the muscle (+2.1±2.3 μMol of deoxygenated-hemoglobin), and NIRS-derived tissue perfusion index showed distinct profiles between the muscle (hypoperfusion) and the brain (hyperperfusion) with prolonged hypoxia. Changes in tissue oxygenation were not associated with cardiorespiratory responses (e.g., HRV, EtCO2) and altitude sickness symptom appearance during hypoxic sessions. These data demonstrate that sustained hypoxia elicits time delay in changes between arterial and tissue (especially cerebral) oxygenation, as well as a tissue-specific sensitivity.