In the face of multiple crises and challenges brought by global change and intensified human activities, how to cope with various risks and maintain system resilience has become one of the important issues of regional sustainable development. The One Belt and One Road initiative is international economic cooperation initiative put forward by China, which aims to promote economic globalization and win-win international cooperation. While, some countries along the One Belt and One Road are in a fragile ecological environment and backward in social and economic development, such as Nepal whose socioeconomic-ecological composite system has potential low risk resistance characteristics. It is crucial to evaluate the spatiotemporal characteristics of the socioeconomic-ecological composite system resilience of typical countries and identify the key factors for the implementation of the "Go Global" strategy and the Green Silk Road construction. Taking Nepal as case study area, an index system for evaluating the resilience of the socioeconomic-ecological composite system was constructed based on five first-level indicators and 24 second-level indicators from the perspectives of social development, economic level, infrastructure construction, ecological environment, and the natural disaster risk. Then, based on principal component analysis and structural equation model, this paper evaluated the resilience of socioeconomic-ecological composite system at county-level in Nepal from 2000 to 2015, analyzed its temporal and spatial variation characteristics, and clarified the key factors influencing the resilience and its influencing mechanism. The results showed that at the county level, the resilience of the socioeconomic-ecological composite system in Nepal was mainly concentrated at the low and medium levels, while the resilience of the middle and high levels gradually decreased from south to north, and the resilience of the southern region and the Capital Kathmandu Valley in the central development zone was relatively high. In addition, from 2000 to 2015, the resilience of socioeconomic-ecological composite system in Nepal fluctuated and showed spatial differences at different stages. The resilience was the highest in 2005, and decreased significantly in some regions in 2010 and 2015, and the regional differences of the system resilience increased gradually. Moreover, the total effects of social development, economic level, infrastructure construction, ecological environment and natural disaster risk on resilience improvement were 0.99, 0.07, 0.11, 0.89 and -0.12, respectively. According to the effect degree of the factors, the key path to enhance Nepal's resilience mainly lay in promoting social and economic development, improving the ecological environment, promoting infrastructure construction and reducing disaster risk. In the future, Nepal should rely on the "One Belt and One Road Initiative" construction platform to strengthen cooperation and exchanges with neighboring countries, improve social security and the balanced regional development, promote industrial upgrading and capital accumulation, develop ecological forestry, strengthen disaster monitoring and decision support system construction, and realize social, economic and ecological coordination and sustainable development.