Abstract: Hepatocellular carcinoma (HCC), one of the most prevalent malignant tumors causing the highest mortality globally, imposes an especially heavy burden of disease in China. Individuals living in high-altitude areas have a lower incidence of and mortality resulting from HCC compared with those in low-altitude regions do, potentially due to adaptive evolution in responses to hypoxic stress. Notably, high-altitude hypoxic stress is associated with the development and progression of HCC. Hypoxic stress may be involved in the development and progression of HCC by modulating the senescence, apoptosis, metabolism, tumor microenvironment, and tumor immunity of HCC cells. Additionally, the latest clinical findings indicate that high-altitude hypoxic environment has a significant impact on liver regeneration after HCC resection surgery. However, there is still a debate going on regarding whether high-altitude hypoxic stress promotes or inhibits the progression of HCC. This review covers three main aspects, the impact of adaptive evolution to high-altitude hypoxic stress on the development and progression of HCC in long-term residents of high-altitude areas, the effects of high-altitude hypoxic stress on the senescence, apoptosis, metabolism, tumor microenvironment, tumor metabolism, and tumor immunity of HCC cells, and the effect of high-altitude hypoxic stress on liver regeneration after HCC resection. We discussed the effect of changes in oxygen concentrations, cellular context, and tissue microenvironment on HCC development and progression. Moreover, we highlighted the potential for using research findings on mechanisms underlying high-altitude hypoxic stress to optimize HCC treatment strategies.