The study examined the interactive effects of a 10-day exposure to hypoxia and bedrest on the whole body peak oxygen uptake (VO2peak) during maximal exercise, and on skeletal-muscle and cerebral oxygenation during submaximal exercise. Nine males underwent three 10-day confinements, in a Latin-square order: i) a normoxic bedrest [NBR; partial pressure of inspired O2 (PIO2) = 134.2±0.7 mmHg], ii) a hypoxic bedrest (HBR; PIO2 = 102.9±0.1 mmHg at day 1, 91.5±1.2 mmHg at days 3-10), and iii) a hypoxic ambulation (HAMB; PIO2 as in HBR). Before, one (R+1) and three (R+3) days after each confinement, subjects performed exhaustive, incremental-load and moderate-intensity constant-load (CLTs) cycle-ergometry trials, while breathing either room air, or a hypoxic gas mixture. During the CLTs, changes in the regional oxygenation of the cerebral frontal cortex, and the vastus lateralis and intercostal muscles were monitored with near-infrared spectroscopy. At R+1, the confinement-related impairment in VO2peak was greater after HBR than after NBR or HAMB, regardless of whether the trial was performed in room-air or hypoxia (HBR: -16.2%, NBR: -8.3%, HAMB: -4.1%; P = 0.001). During the CLTs, bedrest aggravated the exercise-induced reduction in locomotor- and respiratory-muscle oxygenation (P ≤ 0.05); an effect that was less after HBR than after NBR (P ≤ 0.05). The hypoxia exercise-induced cerebral vasodilatatory response was blunted by HBR, likely due to the marked hyperventilation-dependent hypocapnea, attendant to the sustained hypoxic stimulus. Hence, short-term exposure to hypoxia potentiates the reduction in VO2peak, but it mitigates the impairment in skeletal-muscle oxidative capacity induced by bedrest.