The body is more prone to fatigue in a high-altitude hypoxic environment, in which fatigue occurs in both peripheral muscles and the central nervous system (CNS). The key factor determining the latter is the imbalance in brain energy metabolism. During strenuous exercise, lactate released from astrocytes is taken up by neurons via monocarboxylate transporters (MCTs) as a substrate for energy metabolism. The present study investigated the correlations among the adaptability to exercise-induced fatigue, brain lactate metabolism and neuronal hypoxia injury in a high-altitude hypoxic environment. Rats were subjected to exhaustive incremental load treadmill exercise under either normal pressure and normoxic conditions or simulated high-altitude, low-pressure and hypoxic conditions, with subsequent evaluation of the average exhaustive time as well as the expression of MCT2 and MCT4 in the cerebral motor cortex, the average neuronal density in the hippocampus, and the brain lactate content. The results illustrate that the average exhaustive time, neuronal density, MCT expression and brain lactate content were positively correlated with the altitude acclimatization time. These findings demonstrate that an MCT-dependent mechanism is involved in the adaptability of the body to central fatigue and provide a potential basis for medical intervention for exercise-induced fatigue in a high-altitude hypoxic environment.