Natural plants from plateaus have been the richest source of secondary metabolites extensively used in traditional and modern health care systems. They were submitted to years of natural selection, co-evolved within that habitat, and show significant anti-fatigue-related pharmacological effects. However, currently, no review on high-altitude plants with anti-fatigue related properties has been published yet. This study summarized several Chinese traditional high-altitude plants, including Rhodiola rosea L., Crocus sativus L., Lepidium meyenii W., Hippophaerhamnoides L., which are widely used in the Qinghai–Tibet Plateau and surrounding mountains, as well as herbal markets in the plains. Based on phytopharmacology studies, deeper questions can be further revealed regarding how these plants regulate fatigue and related mental or physical disease conditions. Many active derivatives in high-altitude medical plants show therapeutic potential for the management of fatigue and related disorders. Therefore, high-altitude plants significantly relieve central or peripheral fatigue by acting as neuroprotective agents, energy supplements, metabolism regulators, antioxidant, and inflammatory response inhibitors. Their applications on the highland or flatland and prospects in natural medicine are further forecast, which may open treatments to reduce or prevent fatigue-related disorders in populations with sub-optimal health.