Background and purpose The present study aimed to examine how long‐term migration to high‐altitude regions affects mentality and cognition, and the correlation with various physiological and biochemical changes. Methods The WHO Neurobehavioral Core Test Battery, Raven's Standard Progressive Matrices (RSPM) and Pittsburgh Sleep Quality Index questionnaire were used to assess 141 young male subjects who lived in plain regions and 217 young male subjects who had migrated to a 4500 m high‐altitude region and lived there for 1–5 years. Arterial oxyhemoglobin saturation, cerebral tissue oxygenation indices (TOIs), serum S100B and brain‐derived neurotrophic factor (BDNF) were also measured. Results Long‐term migrators to a high‐altitude region exhibited exacerbated mood disorders, retarded color discrimination ability, decreased visual memory capacity, and impaired perceptual motor skill and motion stability. In addition, the migrators exhibited lower RSPM scores and lower sleep quality. Further analyses revealed significant correlations between sleep quality and cerebral TOIs, mood and sleep quality, mood and certain cognitive functions, mood and serum BDNF levels, and RSPM scores and serum S100B levels. Conclusions Long‐term living at high altitudes causes significant impairment of psychological and cognitive function. Cerebral hypoxic extent, sleep quality and biochemical dysfunction are major influencing factors.