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Objective To determine the effects of diffuse oxygen inhalation on hypoxia stress, blood oxygen saturation and human metabolic process in migrants in plateau, and to illustrate the anti-hypoxia effect of a new oxygen supply mode and its possible molecular mechanism. Methods Ten workers who had migrated to a plateau at an altitude of 3 540 m for more than 1 year were recruited as the subjects. They were asked to breathe oxygen in a newly developed accommodation cabin with diffuse oxygen supply for 3 consecutive days, 2 h per day. Their physiological indexes, blood routine indexes and plasma metabolic profiles before and after oxygen intake were measured and compared. Results ① The oxygen concentration was (22.85±0.36)% on the first day, (22.52±0.76)% on the second day and (22.57±1.05)% on the third day during the diffusion oxygen inhalation in the accommodation cabin. ②The oxygen saturation level and pulse rate were significantly increased after oxygen inhalation in the subjects (P < 0.01), but there was no significant change in blood pressure (P>0.05). ③ There were 44 metabolites significantly changed (VIP>1, P < 0.05). Among them, 18 metabolites were identified in the positive ion mode and 27 in the negative ion mode. And 4 major metabolic pathways also had significant changes [impact>0.05, -log10(P)>1.3]. Conclusion Oxygen inhalation via diffuse oxygen supply can effectively improve the capacity of cardiopulmonary oxygen supply, and alleviate the impact of hypoxia and cold environment on human metabolism.