Traversing the Qinghai–Tibetan Plateau, the Sichuan–Tibet Railway is by far the most difficult railway project in the world. The Qinghai–Tibetan Plateau features the most active crustal dynamics on earth, the strongest coupling effects of endogenic and exogenic dynamics, and the environment most sensitive to global climate change. The project area is characterized by extremely cold climate, high elevation and relief, high seismic intensity, high geothermal activity, and high tectonic stress. Consequently, the threat of various disaster risks is ever-present at different stages of the entire life cycle of the Sichuan–Tibet Railway. There is urgent need to systematically study these problems at various levels from the fundamental science to the development of key technologies. This article investigates the different disaster risks recognized during the various stages of construction of the Sichuan–Tibet Railway project, and summarizes the scientific challenges and technical problems faced in relation to disaster risk prevention and control. This work also introduces the scientific deployment and relevant research progress of the Sichuan–Tibet Fund special project initiated by the National Natural Science Foundation of China. Here, we also aim to solve the major fundamental scientific challenges in terms of long-term risk prevention and control during the construction of the Sichuan–Tibet Railway, and lay a theoretical foundation to promote breakthroughs in the bottleneck of key technologies. The scientific challenges addressed in the study of disaster risk associated with the Sichuan–Tibet Railway include the following: The quantitative assessment of the activity of deep-large faults and strong earthquake prediction, the evolution of physical fields in areas of strong tectonic activity, the development mechanisms of tunnel hazards, the slope evolution processes under coupled endogenic and exogenic dynamics in alpine gorges, the impact of climate change on the formation and evolution of surface hazards, and the evolution of extreme wind fields in deep-cut canyons. The technical problems faced in disaster risk prevention and mitigation in relation to the Sichuan–Tibet Railway are as follows: Advanced identification, monitoring, and early warning of geological disasters in mountainous areas with steep and complex terrain; risk analysis, prevention, and control of railway engineering disasters based on their dynamic processes; tunnel engineering hazard monitoring, early warning, risk analysis, prevention, and control technologies; key technologies for emergency response; and the green and resilient railway system and lifecycle risk management. The Sichuan–Tibet Fund special project will include five key research topics: (1) the interior geological structure and dynamic evolution of the eastern plateau; (2) the hazard-inducing mechanisms of coupled internal and external forces in canyons and gullies within plateaus; (3) the cataclysm mechanics of deeply buried long-distance tunnel engineering; (4) risk identification and projection of major disasters affecting the railway; and (5) the integrated management of scientific innovations and super large-scale railway construction. Systematic research is expected to reveal the evolution of earth surface movements and coupled engineering-disturbance related disasters. It will also enable the formation of a comprehensive risk analysis method for major engineering disasters, and promote the development of green, safe, efficient, and resilient engineering disaster risk reduction technologies that will support the disaster risk management during the entire lifecycle of the Sichuan–Tibet Railway.