Context: Environmental hypobaric hypoxia induces several physiological or pathological responses in individuals in high-altitude regions. Salvia przewalskii Maxim (Labiatae) (SPM) is a traditional Chinese herbal medicine and has known antibacterial, antiviral, antioxidant, anti-thrombotic, and anti-depressant activities.Objective: This study examined the antihypoxia effects of SPM in vivo.Materials and methods: The dried and pulverised of SPM was extracted from root crude drug with 70% ethanol with ultrasound. Male Sprague-Dawley rats were divided into three groups (n = 10): normal group, hypoxia group (altitude of 4260 m), and hypoxia + SPM group (altitude of 4260 m, SPM of 1.0 g/kg/day). The experiment persisted for 4 weeks. The mean pulmonary arterial pressure (mPAP), hypoxia-inducible factor-1α (HIF-1α) mRNA, and lung pathology were analysed using pulmonary artery pressure recorder, quantitative polymerase chain reaction, and histopathological analysis. Moreover, the effects of SPM on lung proteomes during hypoxia were observed by a TMT-based proteomic approach.Results: Pre-treatment with SPM decreased mPAP (24.86%) and HIF-1α (31.24%), and attenuated the pathological changes in lung tissues. In addition, a total of 28 proteins were differentially expressed in lung of hypoxia + SPM group (fold change > ± 1.2 and p < 0.05). The differentially altered proteins were primarily associated with antioxidative stress, as evidenced by the downregulated expression of Adh7, Cyp2d1, Plod2, Selenow, ND3, and Fabp1, and fructose metabolism, as evidenced by the downregulated expression of Khk and Aldob.Discussion and conclusions: These results suggested that SPM is a promising drug for antihypoxia. The mechanism of action might be related to increasing antioxidant capacity and inhibiting fructose metabolism.