In high-altitude environments, where the low-pressure and hypoxic conditions prevail, the human body undergoes a series of severe metabolic dysfunctions and stress responses. These adverse circumstances are capable of inducing hypoxia-related damage in multiple organs, thereby not only accelerating the fatigue process but also markedly deteriorating health, reducing the quality of life, and diminishing labor productivity. Fatigue represents one of the most common physiological challenges encountered in high-altitude settings. In recent years, dietary supplements and associated natural products of medicinal and edible origin, such as Phyllanthus emblica, Rhodiola rosea, Lycium barbarum, Cistanche deserticola, and Panax ginseng, have attracted substantial interest. This is attributable to their specific anti-hypoxic fatigue properties, low toxicity, and diverse pharmacological activities. These natural substances, which are characterized by their complex chemical compositions, extensive therapeutic targets, and abundant resources, have a long-standing history and great promise in the prevention and treatment of plateau hypoxic fatigue (PHF), underscoring their substantial potential as medicinal-edible resources. This review commences with an overview of the pathogenesis of PHF and subsequently delves into the mechanisms, bioactive components, and clinical outcomes of medicinal-edible dietary supplements and their related natural products in counteracting PHF. The objective is to furnish a scientific basis and reference for the development and application of drugs, health foods, and functional foods aimed at PHF, thereby facilitating the practice and innovation of medicinal-edible strategies in high-altitude health preservation.