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Most people who have moved to high-altitude areas temporarily suffer from sleep disorders. Sleep deprivation negatively affects not only people's daytime activities but also their health. However, most of the existing nonpharmaceutical intervention methods have the problems of discomfort, restricted movement, or high cost. This study involved the use of an oxygen-rich flow of air in the breathing area during sleep to fight hypoxia and aid with altitude acclimatization when people first traveled to a highland plateau. The associated nasal breathing targeted oxygen supply system (NBTOSS) was designed and optimized by numerical simulation and full-scale experiments. Blood oxygen saturation (SaO2) and pulse rate (PR) monitoring experiments were conducted on subjects exposed to hypoxia at a high altitude (Lhasa, 3646.31 m) with or without assistance from the novel oxygen system and on a lowland plain (Xi'an, 397.5 m) as a comparison. The size of the affected area, concentration target value, and oxygen consumption were used as evaluation indices. Experiments have demonstrated the feasibility of creating an oxygen-enriched microenvironment in breathing area during sleep. The results of the testing showed that the oxygen supply area was uniformly covered and that the degree of hypoxia in subjects was effectively alleviated, with average SaO2 increasing to 95% ± 1%. Maintaining oxygen levels during sleep for temporary residents of high altitudes with less oxygen consumption and minimal oxygen supply costs is discussed to provide a healthy and comfortable oxygen-enriched environment.