In the face of global environmental challenges, sustainable development has received much attention worldwide, and sustainability science has emerged in the 21st century as a globally well-recognized new area of science. Rural sustainability science, as an important part of sustainability science, is a use-inspired science aimed at understanding and improving the dynamic relationship between people and the rural environment from a transdisciplinary and multiscale perspective. In tandem with urban sustainability science, it provides much needed scientific support for dealing with rural decline and promoting rural sustainable development. In this paper, we first discuss the concepts of sustainability, rural sustainability, and rural sustainability science, and then propose a transdisciplinary integrated framework of rural sustainability science that focuses on agricultural sustainability, community sustainability, and rural human well-being. China is a nation with deep rural roots, complex problems involving interactions among agriculture, farmers, and villages, and huge urban-rural socioeconomic gaps. Since the reform and opening-up in 1978, China's rural areas have developed rapidly, but they still face numerous tough challenges. Rural revitalization strategies are needed for promoting the rural transition toward sustainability, but the necessary scientific basis and appropriate guidelines for formulating such strategies are still lacking. We argue that rural sustainability science can provide theoretical, technical, and decision-making support for the implementation of rural revitalization strategies. Our analysis of the current status of China's rural sustainable development indicates that the transition to sustainability is urgently needed, and so is the science that guides the transition. To address these problems, we call for transdisciplinary research that couples rural society and its environment, focusing on nine core issues in line with the needs of China's rural development and aiming to transfer knowledge of rural sustainability into local adaptive actions.