Purpose: While acute hypoxic exposure enhances exercise-induced central fatigue and can alter corticospinal excitability and inhibition, the effect of prolonged hypoxic exposure on these parameters remains to be clarified. We hypothesized that 5 days of altitude exposure would (i) normalize exercise-induced supraspinal fatigue during isolated muscle exercise to sea level (SL) values and (ii) increase corticospinal excitability and inhibition. Methods: Eleven male subjects performed intermittent isometric elbow flexions at 50% of maximal voluntary contraction to task failure at SL and after 1 (D1) and 5 (D5) days at 4350 m. Transcranial magnetic stimulation and peripheral electrical stimulation were used to assess supraspinal and peripheral fatigues. Pre-frontal cortex and biceps brachii oxygenation was monitored by near-infrared spectroscopy. Results: Exercise duration was not statistically different between SL (1095 ± 562 s), D1 (1132 ± 516 s), and D5 (1440 ± 689 s). No significant differences were found between the three experimental conditions in maximal voluntary activation declines at task failure (SL −16.8 ± 9.5%; D1 −25.5 ± 11.2%; D5 −21.8 ± 7.0%; p > 0.05). Exercise-induced peripheral fatigue was larger at D5 versus SL (100 Hz doublet at task failure: −58.8 ± 16.6 versus −41.8 ± 20.1%; p < 0.05). Corticospinal excitability at 50% maximal voluntary contraction was lower at D5 versus SL (brachioradialis p < 0.05, biceps brachii p = 0.055). Cortical silent periods were shorter at SL versus D1 and D5 (p < 0.05). Conclusions: The present results show similar patterns of supraspinal fatigue development during isometric elbow flexions at SL and after 1 and 5 days at high altitude, despite larger amount of peripheral fatigue at D5, lowered corticospinal excitability and enhanced corticospinal inhibition at altitude.