The Belt and Road Initiative was first proposed by Chinese President Xi Jinping during his visit to Kazakhstan in 2013 in order to strengthen economic ties, deepen mutual cooperation, and widen the field of development. The Silk Road Economic Belt has cultural connotations of the ancient Silk Road, a regional cooperation strategy between the Asian and African continents. This belt is important for the promotion of the Chinese economy and the development of economic and trade cooperation between China and countries located along the route. However, the Silk Road Economic Belt passes through the harshest geographical and climatic conditions in the world. The region contains complex geological structures, and is characterized by frequent earthquake activity, large differences in terrain elevation, poor engineering geological conditions, as well as intensive rainfall caused by a monsoon climate. As a result, different kinds of natural disasters, such as earthquakes, geo-hazards, floods, droughts, and dammed lakes, seriously hinder in-depth cooperation and communication between countries located along the Silk Road Economic Belt. This paper presents research on the Silk Road Economic Belt. Primary and secondary natural hazards related to geological events and climate change, such as earthquakes, climatic hazards, and geo-hazards triggered by earthquakes and extreme climatic changes, are analyzed. According to the inventory map of earthquakes, droughts, and geo-hazards, the earthquake-prone areas in this region include Central and Western Asia, the Sino-Pakistan Economic Corridor, the Sino-Mongol-Russia Junction Belt, and the New Euro-Asian Continental Bridge. The flood-prone region is located mainly in Southeastern Asia, in countries such as India, Bangladesh, and Myanmar, while the drought-prone region is located primarily in Inner Asia. The region most susceptible to geo-hazards is the mountainous area around the Tibet Plateau. The tendency of frequent natural hazards to develop and their effects on major projects along the Silk Road Economic Belt are discussed in detail. The results show that seismic activity is likely to be high until approximately 2050 and will become relatively quiescent in the second half of the 21st century. Precipitation will increase by 2%–3% until 2020, and by 5%–7% until 2050. Three high-frequency snow hazard regions are formed, including the central area of Inner Mongolia, the northern region of the Xinjiang Tianshan Range, and the Northeastern Tibet Plateau. Although the inter-annual variability of snow hazards changes significantly, the general trend shows an increase. Drought hazards have become more severe in the Qinghai-Tibet Plateau and have expanded in recent years due to global climate change and other factors. Secondary natural hazards have increased due to the rise in earthquake activity and extreme climatic changes. Strategies for disaster mitigation and natural hazards risk analysis are proposed for major projects such as high-speed railways, oil and gas pipelines, and water and electricity infrastructure. In order to reduce the risk of natural hazards and major construction, six countermeasures are proposed: (1) to perform detailed field investigations and build a database of hazards and related data, including climatic, hydrological, topographical, and geological settings; (2) to integrate engineering protection techniques against natural hazards and develop new mitigation techniques; (3) to develop a space-, sky-, and earth-based real-time monitoring and early warning system; and (4) to comprehensively assess the risk of natural hazards and major project construction. In addition, we face five key scientific and administration challenges regarding the safety of major project construction along the Silk Road Economic Belt: (1) formation mechanisms of large-scale natural hazards; (2) trend and forecast of natural hazards along the Silk Road Economic Belt in the context of climatic change; (3) dynamic and quantitative risk assessment of mega-hazards triggered by the coupling of endogenic and exogenic forces; (4) key techniques and an integrated system for risk reduction for major projects; and (5) coordination mechanism for information sharing and mitigation against mega-hazards among multiple countries.